tbuckley/cabot-search huggingface dataset:
Overall survival result and outcomes by <i>KRAS</i>, <i>BRAF</i>, andDNA mismatch repair in relation to primary tumor site in colon cancers from a randomized trial of adjuvant chemotherapy: NCCTG (Alliance) N0147.
Authors: Frank A. Sinicrope, Harry H. Yoon, Michelle R. Mahoney, Garth D. Nelson, Stephen N. Thibodeau, Richard M. Goldberg, Daniel J. Sargent, Steven R. Alberts
Journal: Journal of Clinical Oncology (2014)

3525 Background: We report mature overall survival (OS) data in stage III colon cancers from a phase III trial of adjuvant mFOLFOX6 ± cetuximab. Biomarkers were analyzed in relation to primary tumor site and OS, and include additional non randomized patients (pts) with KRASmutant tumors. Methods: Cancers (N= 3,018) were analyzed prospectively for BRAFV600E (exon 15) and KRAS (exon 2;codons 12, 13) mutations, and expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2, and MSH6). Loss of an MMR protein indicated deficient (d) MMR. Tumor site was categorized as proximal vsdistal (inclusive of the splenic flexure). Median follow-up was 4.9 yrs. Cox proportional hazards models were adjusted for covariates including treatment. Results: Consistent with our previously reported DFS data, the addition of cetuximab was associated with worse OS in pts with wild type KRAS (p=.0073). Activating BRAFV600E or KRAS mutations were detected in 346/2831 (12.2%) and 1042/2905 (35.9%) tumors, respectively; dMMR was found in 329/2906 (11.3%). dMMR or mutations in BRAFV600E or KRAS were more likely to occur in proximal vs distal tumors [all p<.0001]. BRAFV600E mutations were associated with older age, female sex, high grade histology, dMMR, and higher T and N stage (all p< 0.01). A tumor site interaction was observed for OS with KRAS (p=.0435) and MMR (p=.0097), but not BRAF. KRAS mutations [HR 1.98 (1.49-2.63); p<.0001] and dMMR [HR 1.85 (0.99-3.46); p=.054] were each associated with worse OS in distal (vs proximal) cancers. dMMR predicted favorable OS in proximal tumors [HR 0.71 (0.53-0.97); p=.030]. Tumors with wild type copies of both BRAF and KRAS showed better OS within proximal [HR 0.74 (0.59-0.93); p=.009] and distal [HR 0.51 (0.39-0.67); p<.0001] cancers compared to those with a BRAFV600E or KRASmutation. Conclusions: The addition of cetuximab to mFOLFOX6 resulted in significantly poorer OS. The prognostic impact of biomarkers on OS differed significantly by tumor site. Novel findings include poor OS of KRAS mutant tumors that was restricted to the distal colon, and a divergent prognosis for dMMR by primary tumor site. Clinical trial information: NCT00079274.
Sustained Psoriasis Area and Severity Index, Dermatology Life Quality Index and EuroQol‐5D response of biological treatment in psoriasis: 10 years of real‐world data in the Swedish National Psoriasis Register
Authors: F. Hjalte, K.S. Carlsson, M. Schmitt‐Egenolf
Journal: British Journal of Dermatology (2017)

Few studies have analysed the long‐term effects of biological treatment in psoriasis. PsoReg, the Swedish national register for systemic psoriasis treatment, started in 2006 and now includes 10 years of real‐world data on the effectiveness of biological treatment. To analyse the long‐term real‐world outcome data of patients who are biologically naïve with moderate‐to‐severe psoriasis after switching to biological treatment. An observational study of patients who are biologically naïve with at least one registration of outcome before switching to biological treatment while included in PsoReg and at least one follow‐up visit. Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and EuroQol‐5D (EQ‐5D) values were analysed at 3–5 months, 6–11 months and at least once after ≥ 1 year, up to 9 years after the switch to biological treatment. In total, 583 patients fulfilled the inclusion criteria. Of these, 399, 395 and 373 patients had observed outcome data beyond 1 year on the PASI, DLQI and EQ‐5D, respectively, and 164, 168 and 152, respectively, were observed in at least three time periods after the switch. Significant (P < 0·01) improvement in PASI, DLQI and EQ‐5D scores was observed 3–5 months after the switch and sustained under the whole observation period. The mean PASI, DLQI and EQ‐5D changed from 13·5 ± 9·1, 9·0 ± 8·1 and 0·74 ± 0·22, respectively, before the switch, to 4·0 ± 3·5, 3·7 ± 4·7 and 0·79 ± 0·21, respectively, 1–5 years after the switch. Biological treatment, as used in clinical practice, shows a stable long‐term effectiveness in all the measured dimensions, PASI, DLQI and EQ‐5D.
Guidelines for the laboratory diagnosis of genital herpes in eastern European countries
Authors: M Domeika, M Bashmakova, A Savicheva, N Kolomiec, E Sokolovskiy, A Hallén, M Unemo, R C Ballard, None Eastern European Network for Sexual
Journal: Eurosurveillance (2010)

These guidelines aim to provide comprehensive information about sexually transmitted herpes simplex virus (HSV) infection and its laboratory diagnosis in eastern European countries. They are primarily intended for professionals testing specimens from patients at a sexual healthcare clinic but may also be helpful for community-based screening programmes. In particular, the guidelines recommend: (i) either viral culture or validated and approved nucleic acid amplification tests (NAATs) as the tests of choice for symptomatic patients, which should be promoted for laboratory confirmation of HSV infection; (ii) if culture or NAATs are not available, antigen detection - a direct immunofluorescence test or enzyme immunoassay from samples from symptomatic patients - could be employed, but HSV type determination is of importance; (iii) only type-specific serology should be used for detecting asymptomatic individuals, testing pregnant women at risk of acquiring HSV infection close to delivery, men who have sex with men and people who are HIV positive; (iv) widespread screening for HSV antibodies should be discouraged; and (v) any non-validated diagnostic tests should be validated against a recommended, approved gold standard. .
Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals
Authors: Yang Qiu, Yanpeng Xu, Yao Zhang, Hui Zhou, Yong-Qiang Deng, Xiao-Feng Li, Meng Miao, Qiang Zhang, Bo Zhong, Yuanyang Hu, Fu-Chun Zhang, Ligang Wu, Cheng-Feng Qin, Xi Zhou
Journal: Immunity (2017)
Analysis of Newly Identified and Rare Synonymous Genetic Variants in the RET Gene in Patients with Medullary Thyroid Carcinoma in Polish Population
Authors: Maria Sromek, Małgorzata Czetwertyńska, Magdalena Tarasińska, Aneta Janiec-Jankowska, Renata Zub, Maria Ćwikła, Dorota Nowakowska, Magdalena Chechlińska
Journal: Endocrine Pathology (2017)
In-depth Characterization of a TCR-specific Tracer for Sensitive Detection of Tumor-directed Transgenic T Cells by Immuno-PET
Authors: Nahid Yusufi, Sabine Mall, Henrique de Oliveira Bianchi, Katja Steiger, Sybille Reder, Richard Klar, Stefan Audehm, Mona Mustafa, Stephan Nekolla, Christian Peschel, Markus Schwaiger, Angela M Krackhardt, Calogero D`Alessandria
Journal: Theranostics (2017)

A number of different technologies have been developed to monitor in vivo the distribution of gene-modified T cells used in immunotherapy.Nevertheless, in-depth characterization of novel approaches with respect to sensitivity and clinical applicability are so far missing.We have previously described a novel method to track engineered human T cells in tumors using 89 Zr-Df-aTCRmu-F(ab')2 targeting the murinized part of the TCR beta domain (TCRmu) of a transgenic TCR.Here, we performed an in-depth in vitro characterization of the tracer in terms of antigen affinity, immunoreactivity, influence on T-cell functionality and stability in vitro and in vivo.Of particular interest, we have developed diverse experimental settings to quantify TCR-transgenic T cells in vivo.Local application of 89 Zr-Df-aTCRmu-F(ab')2-labeled T cells in a spot-assay revealed signal detection down to approximately 1.8x10 4 cells.In a more clinically relevant model, NSG mice were intravenously injected with different numbers of transgenic T cells, followed by injection of the 89 Zr-Df-aTCRmu-F(ab')2 tracer, PET/CT imaging and subsequent ex vivo T-cell quantification in the tumor.Using this setting, we defined a comparable detection limit of 1.0x10 4 T cells.PET signals correlated well to total numbers of transgenic T cells detected ex vivo independently of the engraftment rates observed in different individual experiments.Thus, these findings confirm the high sensitivity of our novel PET/CT T-cell tracking method and provide critical information about the quantity of transgenic T cells in the tumor environment suggesting our technology being highly suitable for further clinical translation.
CD8 positive tumour infiltrating lymphocytes (TILS) are increased in early stage colorectal cancer (CRC)
Authors: LM Wang, E Fox, D Leahy, J O'Sullivan, R Geraghty, H Mulcahy, J Hyland, DP O'Donoghue, K Sheahan
Journal: Endoscopy (2006)

Methods: Tissue microarrays (TMAs) were assembled from formalin-fixed tissue in 77 randomly selected sporadic CRC cases, previously classified as MSI-H (high), MSI-L (low) and MSS (stable). Sections were stained immunohistochemically using an anti-CD8 T cell antibody. The number of CD8+ T lymphocytes (CD8+ TILs) within tumour epithelium was assessed by counting the area of each tissue core under high-power field (x40 objective). The results were correlated with age, gender, & standard pathological parameters including Dukes stage, TNM stage, lymphovascular & neural invasion and MSI status.
Development of practice algorithms to guide treatment planning with TTFields for the management of glioblastoma (GB).
Authors: Erin M. Dunbar, Fabio Massaiti Iwamoto, John E. Trusheim, Nimish Mohile, James Battiste, Jennifer Marie Connelly, Denise Damek, Daniela Annenelie Bota
Journal: Journal of Clinical Oncology (2016)

e13519 Background: TTFields are a key modality in the management GB, and are delivered to patients in 2 paired orthogonal planes via direct application of transducer arrays to the shaved scalp. Array placement is planned through the NovoTAL software using MRI morphometric head size and tumor location measurements. As TTFields non-uniformly distribute through the brain parenchyma, treatment planning aims to optimize field intensity delivered to the tumor. Tumor location is obtained from fixed origins at the level of the scalp to the borders of active tumor in axial and coronal views. GB can be radiographically heterogeneous, presenting with enhancing and/or nonenhancing areas on imaging. Newly diagnosed GB patients may receive TTFields following a gross total resection with no post-op MRI enhancement. Interpreting imaging in recurrent GB may be complicated due to the effects of prior therapies and patterns of recurrence. Thus, clinical guidance is needed for physicians to appropriately plan TTFields across a spectrum of clinical scenarios. Methods: Neuro-oncologists with significant collective TTFields planning experience (mean 31, range 15-68 cases in 2015) collaboratively developed TTFields treatment planning algorithms, which have been prospectively incorporated into practice guidelines developed for the multi-disciplinary team caring for GB patients. Results: Comprehensive treatment planning algorithms were developed for enhancing and non-enhancing tumors in the newly diagnosed and recurrent GB settings, for multi-focal and gross totally resected tumors, and for assessing response to therapy in these various clinical scenarios. Guidance has also been developed for re-planning therapy based on sequential imaging changes. Conclusions: TTFields in combination with TMZ have improved overall survival in newly diagnosed GB. As TTFields become increasingly incorporated into standard GB management, clinical practice guidelines are acutely needed in order to optimize efficacy and outcomes via standardization of treatment across patients and institutions. The development of these algorithms represents the first-ever clinical practice guidelines for the use of TTFields in GB.
Abstract 228: CaMKII as a Link Between Inflammation and Fibrosis Induced by Chronic Isoproterenol and Angiotensin II Treatment
Authors: Andrew Willeford, Joan Heller Brown
Journal: Circulation Research (2015)

The Ca2+/calmodulin-dependent kinase, CaMKIIδ, is an established mediator of the development of heart failure and myocardial injury. Cardiac inflammation has been increasingly recognized as an important player in these cardiac pathophysiological changes. We previously demonstrated that CaMKIIδ contributes to cardiac inflammation induced by ischemia/reperfusion through activation of cardiomyocyte NF-kB. In the current study we ask whether angiotensin II (Ang II) and isoproterenol (ISO), both known to activate CaMKII, promote cardiac inflammation through this protein kinase and its effects on NF-kB activation. In addition, chronic ISO and Ang II treatment promote cardiac fibrosis and we hypothesize that this response is initiated through activation of CaMKIIδ and subsequent inflammatory responses. We report on our recent findings that show attenuated inflammatory cytokine expression (e.g. IL-6, MCP1, and TNFα) in response to 7 days Ang II infusion in mice in which CaMKIIδ is specifically deleted in cardiomyocytes (cardiac specific knockout; CKO). In addition the expression of fibrotic markers (e.g. col1a1, col3a1, and CTGF) in response to Ang II infusion is decreased in the CKO mice. This is associated with attenuated fibrosis as evident in histological analysis of CKO vs WT heart sections. Ongoing studies will compare the effects of chronic ISO and Ang II in CKO and WT mice to determine whether inflammation precedes fibrosis and assess the extent to which apoptosis induced by CaMKII activation plays a part in these responses. Currently, we are determining whether Ang II and ISO act through CaMKII to activate NF-kB in the cardiomyocyte compartment to induce proinflammatory and profibrotic factors and whether preventing the expression of these factors block development of further inflammatory and fibrotic responses. Findings from these studies may implicate CaMKII as a promising therapeutic target for attenuating cardiac fibrosis.
Long-adapter single-strand oligonucleotide probes for the massively multiplexed cloning of kilobase genome regions
Authors: Lorenzo Tosi, Viswanadham Sridhara, Yunlong Yang, Dongli Guan, Polina Shpilker, Nicola Segata, H. Benjamin Larman, Biju Parekkadan
Journal: Nature Biomedical Engineering (2017)
The impact of multidisciplinary review at two weeks following resectional surgery of oesophago-gastric malignancies
Authors: N Laking, P Vassallo, H Williams, SA Wilson, PA Davis, YKS Viswanath
Journal: Endoscopy (2005)

Introduction: Late complications can occur following uncomplicated recovery after oesophagectomy and gastrectomy. We, in this study, evaluated the benefits to patients and carers of multidisciplinary outpatient review two weeks following discharge.
Treatment outcomes with first-line (1L) <i>nab</i>-Paclitaxel + gemcitabine (AG) and FOLFIRINOX (FFX) in metastatic pancreatic adenocarcinoma (mPAC).
Authors: Thomas H. Cartwright, Monika Parisi, Janet L. Espirito, Thomas Wilson, Corey Pelletier, Manish Patel, Hani M. Babiker
Journal: Journal of Clinical Oncology (2017)

e18147 Background: AG and FFX have demonstrated improved overall survival (OS) compared to gemcitabine (GEM) as 1L treatment (tx) for mPAC. Limited comparative data exists on AG vs FFX. This study compared time to treatment failure (TTF), OS, and patient (pt) demographics in mPAC pts receiving 1L AG vs FFX, and evaluated outcomes by performance status (PS) in a real-world setting. Methods: This was a retrospective observational cohort study of adult pts diagnosed with stage IV mPAC treated with 1L AG, FFX, or GEM monotherapy between 04/2013 and 10/2015 with at least 3 mo follow-up, to 01/2016. We report results for AG vs FFX; AG vs GEM analysis is ongoing. Data were programmatically extracted from the iKnowMed electronic health record database of pts in The US Oncology Network. Eligibility included ≥3 doses of A (for AG) or ≥2 doses of fluorouracil (for FFX), and excluded pts on clinical trial or with other cancer diagnoses during the study period. Categorical variables were compared with chi-squared tests. TTF and OS were assessed using the Kaplan-Meier method. Results: 2,901 pts with mPAC receiving chemotherapy during the study period were initially identified. 486 total pts met all eligibility criteria, with 255 AG and 159 FFX pts. Median age was 68 and 61 yrs for AG and FFX respectively (p &lt; .0001). ECOG PS was 0-1 in 77% of AG pts and 91% of FFX pts (p = 0.0004). Median TTF and mOS in all pts was 3.5 [95% CI 3.0-3.9] and 9.8 mo [95% CI 8.2-11.5] respectively. There was no statistical difference in mTTF or mOS for the AG vs FFX cohorts (mTTF 3.7 vs 4.3 mo, log-rank p = 0.25; and mOS 9.8 vs 11.4 mo, log-rank p = 0.38). Among pts with ECOG PS 0-1, TTF for AG vs FFX was 4.2 vs 4.3 mo respectively (log-rank p = 0.47); and OS for AG vs FFX was 12.1 vs 11.4 mo (log-rank p = 0.68). Conclusions: Although pts in the AG cohort were older and had worse PS, mTTF and mOS were not statistically different from pts in FFX. Results were similar after stratifying by PS. Limitations include the retrospective and non-randomized nature of the study. However, this represents real world outcomes where randomized data do not exist. Analysis of toxicities and resource utilization is ongoing and will aid in optimizing tx selection in these pts.
Phase II study of weekly paclitaxel and carboplatin followed by oral navelbine in patients with triple negative metastatic/recurrent breast cancer previously treated with adjuvant anthracycline and taxotere.
Authors: Inas Ibraheim Abdel Halim, Wael El-Sadda, Mostafa El-Ebrashy, Mohamed El Ashry
Journal: Journal of Clinical Oncology (2016)

e12557 Background: Triple negative breast cancer (TNBC) is defined by the lack of expression of the ER, PR & HER2. Metastatic TNBC is an aggressive subtype of breast cancer marked by higher rates of visceral and CNS metastasis as well as poor survival. Recent data suggest that TNBC have increased sensitivity to platinum agents. The purpose of this study is to evaluate weekly paclitaxel and carboplatin followed by oral navelbine in patients with metastatic/recurrent TNBC in terms of response rate, toxicity profile, progression free survival and over all survival. Methods: Between December 2011–December 2013; 50 patients with measurable metastatic/recurrent TNBC, after adjuvant anthracycline & taxotere treatment, were included in the study. Patients had WHO PS < 2, adequate renal, liver and bone marrow functions. All patients received weekly paclitaxel 80mg/m2 D1, D8, D15 (one hour IV infusion) and carboplatin AUC 5 D1 (IV infusion over 30 minutes) every 4 weeks for 6 cycles, response was assessed every 2 cycles, patients showed an objective response (CR, PR or SD) had continued 8 cycles followed by oral navelbine 60 mg/m2 D1 & D8 for 1st cycle then 80 mg/m2 D1 & D8 every 3 weeks for 6 months. Results: All Patients were evaluated for response, toxicities and survival. Median age 42 years (range 36-55) and median WHO PS 0. Main metastatic sites were lung 40%, liver 30%, skin12%, bone 50%, local recurrence 30%. Forty percentage of patients had one metastatic site, 40% had 2 metastatic sites and 20% had > 2 metastatic sites. The overall response rate after paclitaxel/carboplatin was 60% (CR 10%, PR 50%), SD 26%, PD 14% while after oral navelbine, the ORR was 74.4% (CR 23.2%, PR 51.2%), SD 16.3% & PD 9.3%. The median PFS & OS were 11.3 & 18.8 months respectively. No grade 4 toxicity, G3 neutropenia observed in 12% of patients, G2 neuropathy and G2 anemia were occurred in 14% of patients. Conclusions: Weekly paclitaxel and carboplatin followed by oral navelbine is an effective, safe & tolerable regimen in patients with metastatic/recurrent TNBC previously treated with adjuvant anthracycline & taxotere, with ORR 74.4%.
Commentary: Interactivity and case learning
Authors: Ed Peile
Journal: BMJ (2006)

The volume of online response to this interactive case report has been disappointing.1 This prompted me to reflect on the nature of interactivity in online learning and in learning in general.

Learners' engagement with, and participation in, educational learning activities is widely accepted to enhance their learning. There is also evidence that in group activities, learning for peers is enhanced by participation of others. So if interactivity is beneficial, how do we encourage this participation, be it with published cases, with material on a website, or in live lectures, ward rounds, or clinic teaching?

A starting point is to consider the nature of interaction. In this series, for example, we have seen doctors engaging cognitively at several levels (box). Informal discussion suggests that for each person who files a rapid response, many more engage with the material and reflect on it but do not interact publicly. There may be many reasons for this, ranging from reticence and fear of appearing stupid to lack of time or opportunity. There is scope for research here, as cases that prompt a large volume of response seem to show much active learning, and your comments would be welcome.
Prognostic and therapeutic implications of fibroblast growth factor receptors (FGFRs) 1 and 2 gene amplifications in patients (pts) with advanced breast cancer (ABC).
Authors: Fabricio Eugenio Racca, Ester Zamora, Eva Muñoz-Couselo, Paolo Nuciforo, Meritxell Bellet, Vicente Peg, Cristina Saura, Ana Vivancos, Roberta Fasani, Mafalda Oliveira, Isabel T Rubio, Marta Vilaro, Patricia Gomez, Ludmila Prudkin, Maria Vidal, Jesus Soberino, Alba Meire, Vanesa Ortega, Javier Cortes, Jose Manuel Perez-Garcia
Journal: Journal of Clinical Oncology (2016)

537 Background: Fibroblast growth factors (FGFs) and FGFRs play an essential role in cancer cell proliferation and survival, with FGFR1 and FGFR2 gene amplifications being the most frequent genomic aberrations identified in ABC. In this study, we sought to investigate the prognostic and therapeutic implications of FGFR1 and FGFR2 in pts with ABC. Methods: All pts with ABC analyzed for FGFR1 and/or FGFR2 gene amplification by FISH at the Vall d'Hebron Molecular Pathology and Genomics Labs between 2010 and 2014 were included in the study. Amplificationwas defined asa geneto copy number controlratioof ≥2.2. Results: FGFR1 and FGFR2 gene amplifications were detected in 47/205 (22.9%) and 3/67 (4.5%) pts, respectively.No significant differences in clinicopathologic features were found according to FGFR1 gene status. FGFR1 gene amplification was not associated with poorer disease-free survival (DFS) (2.9 versus 4.2 years; p = 0.097) or overall survival (OS) (8.6 versus 10.4 years; p = 0.550), but it was associated with shorter time to progression during first-line hormonal therapy (3.3 versus 11.9 months; p = 0.039). FGFR2 gene amplification was not associated with poorer DFS (1.4 versus 3.2 years; p = 0.140), but it was associated with shorter OS (2.6 versus 10.2 years; p = 0.002). The overall concordance rate of FGFR1 and FGFR2 gene amplification status in 16 and 13 pts with paired samples from the primary tumor and the metastatic site was high (87.5% and 100%, respectively). PIK3CA mutations were the most common genetic alteration detected in all pts (27.4%). The proportion of pts with FGFR1 gene amplification and PIK3CA mutation was 20%. A total of 25 pts (12.2%) included in the study were treated with FGFR inhibitors in a clinical trial, corresponding to 42.1% of all FGFR1-amplified pts, with an overall response rate of 12.9%. Conclusions: FGFR1 and FGFR2 gene amplifications have important prognostic and therapeutic implications for pts with ABC. Additional studies are needed to better define the role of FGFR2 gene amplification as well as the antitumor activity of FGFR inhibitors in ABC pts, especially in combination with endocrine therapy.