tbuckley/cabot-search huggingface dataset:
Identification of novel therapeutic targets in glioblastoma with functional genomic mRNA profiling.
Authors: Cyrillo Gerardo Brahm, Anna Maria Elisabeth Walenkamp, Myra Ellen Van Linde, Henk M.W. Verheul, Rudolf Stephan Nicolaas Fehrmann
Journal: Journal of Clinical Oncology (2017)

2018 Background: Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs and has a dismal prognosis. Therefore, there is an unmet need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets by identifying upregulated genes in GBM with known antineoplastic drug interactions. Methods: Publicly available, raw microarray expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we applied functional genomic mRNA profiling (FGmRNA-profiling), a method that is able to correct the gene expression profile of an individual tumor for physiological and experimental factors, which are considered not to be relevant for the observed tumor phenotype. Next, the FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: known interaction with antineoplastic agents and the current status of clinical evaluation in humans. Results: After FGmRNA-profiling 66 normal brain tissue samples and 1280 patient-derived GBM samples, class comparison identified 712 significantly upregulated genes. Of all significantly upregulated genes, 27 genes interacted with antineoplastic drugs. 17 out of these 27 druggable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM, and had limited efficacy. Out of the 10 remaining druggable genes, we prioritized RRM2, MAPK9 and XIAP, as these genes are associated with biologic pathways involved in the carcinogenesis of GBM and are therefore considered as novel potential therapeutic targets. Conclusions: Based on data-driven prioritization, we identified three potential therapeutic druggable targets, which have not yet been explored in the context of glioblastoma. Further preclinical and clinical research on the inhibition of these druggable genes is necessary and may lead to an improvement of treatment outcomes for patients with GBM.
Efficacy of Pegaspargase, Etoposide, Methotrexate and Dexamethasone (PEMD) in Newly-Diagnosed Advanced-Stage Extra-Nodal Natural Killer (NK)/T-Cell Lymphoma
Authors: Wei Xu, Jin-Hua Liang, Li Wang, Lei Fan, Hua-Yuan Zhu, Jian-Yong Li
Journal: Blood (2016)
Subcutaneous trastuzumab therapy for HER2-positive early breast cancer in the routine clinical practice: First interim analysis of the National Non-Interventional Study (NIS) HerSCin.
Authors: Marcus Schmidt, Sherko Kummel, Antonia Ruf-Doerdelmann, Andrea Distelrath, Juergen Wacker, Sabine Schmatloch, Stella Keitel, Kerstin Luedtke-Heckenkamp
Journal: Journal of Clinical Oncology (2016)

581 Background: In 2013 a subcutaneous (SC) formulation of trastuzumab (T) was approved based on non-inferiority to intravenous (IV) T as proven in the HannaH trial. So far no data from the routine clinical use of T SC have been published yet. Methods: The NIS HerSCin is investigating the efficacy, safety, tolerability and patient reported quality of life (QoL) of (neo-)adjuvant T SC use in routine clinical practice in Germany. Since 11/2013 a total of 960 patients (pts) have been enrolled at 187 sites. Primary endpoints are pathological complete response (pCR) in the neoadjuvant setting and disease-free survival after two years in the adjuvant setting. Secondary endpoints include adverse events (AEs), QoL, details of T SC administration and 2-year event free survival. Treatment decisions were at physician’s discretion. Retrospective enrolment was possible up to 9 weeks after initiation of T SC therapy. Results: 130 pts were included in this preliminary analysis after completion of the treatment phase. 86% of pts (n = 112) received adjuvant and 14% (n = 18) received neoadjuvant therapy. Mean age of all pts was 57 years and 97% (n = 113/117) had an ECOG performance status of ≤ 1. The majority of tumors were G2 and G3 (45% and 50%), respectively. 48% (n = 60/126) of pts had a T1 tumor, 39% (n = 49/126) presented with a T2 lesion. Nodal status was negative in 58% (n = 72/125) of the cases. Estrogen receptor status was positive in 64% (n = 82/129) of pts and progesterone receptor status was positive in 54% (n = 70/129). Median duration of T SC treatment (neoadjuvant and adjuvant) for this analysis was 8.5 months. Of the pts receiving neoadjuvant treatment (n = 18), 33% achieved a pCR. AEs of any grade and of ≥ grade 3 were reported for 59% (n = 77/130) and 15% (n = 19/130) respectively. To date, 17% (22/130) of pts had at least one AE related to T SC; 2% (2/130) had a serious AE related to T SC; and 8% (10/130) had an AE that led to withdrawal or interruption of T SC treatment. One death was reported but this event was not related to T SC. Conclusions: Updated Efficacy and safety results for T SC from a greater number of pts will be available as of March 2016 and will be presented at the meeting. Clinical trial information: NCT01959386.
ILC2-modulated T cell–to-MDSC balance is associated with bladder cancer recurrence
Authors: Mathieu F Chevalier, Sara Trabanelli, Julien Racle, Bérengère Salomé, Valérie Cesson, Dalila Gharbi, Perrine Bohner, Sonia Domingos-Pereira, Florence Dartiguenave, Anne-Sophie Fritschi, Daniel E Speiser, Cyrill A Rentsch, David Gfeller, Patrice Jichlinski, Denise Nardelli-Haefliger, Camilla Jandus, Laurent Derré
Journal: Journal of Clinical Investigation (2017)

Non-muscle-invasive bladder cancer (NMIBC) is a highly recurrent tumor despite intravesical immunotherapy instillation with the bacillus Calmette-Guérin (BCG) vaccine. In a prospective longitudinal study, we took advantage of BCG instillations, which increase local immune infiltration, to characterize immune cell populations in the urine of patients with NMIBC as a surrogate for the bladder tumor microenvironment. We observed an infiltration of neutrophils, T cells, monocytic myeloid-derived suppressor cells (M-MDSCs), and group 2 innate lymphoid cells (ILC2). Notably, patients with a T cell-to-MDSC ratio of less than 1 showed dramatically lower recurrence-free survival than did patients with a ratio of greater than 1. Analysis of early and later time points indicated that this patient dichotomy existed prior to BCG treatment. ILC2 frequency was associated with detectable IL-13 in the urine and correlated with the level of recruited M-MDSCs, which highly expressed IL-13 receptor α1. In vitro, ILC2 were increased and potently expressed IL-13 in the presence of BCG or tumor cells. IL-13 induced the preferential recruitment and suppressive function of monocytes. Thus, the T cell-to-MDSC balance, associated with a skewing toward type 2 immunity, may predict bladder tumor recurrence and influence the mortality of patients with muscle-invasive cancer. Moreover, these results underline the ILC2/IL-13 axis as a targetable pathway to curtail the M-MDSC compartment and improve bladder cancer treatment.
Abstract 9323: Localized Reentrant Activation in the Left Atrium During Human Atrial Fibrillation: Relationship to Complex Fractionated Atrial Electrograms and Low Voltage Zones
Authors: Behnaz Ghoraani, Rupin Dalvi, Sigfus Gizurarson, Moloy Das, Alexander Martin, Andrew Ha, Adrian Suszko, Sridhar Krishnan, Vijay S Chauhan
Journal: Circulation (2013)

Introduction: In humans, the existence of reentrant sources maintaining AF and the underlying electroanatomic substrate has not been well defined. Our objective was to determine the prevalence of localized reentrant activation in the left atrium (LA) during human AF and whether complex fractionated atrial electrograms (CFAEs) or low voltage areas co-localize with these sites. Methods: We prospectively studied 32 patients (57±8yrs, 88% persistent AF) undergoing AF catheter ablation. Bipolar EGMs were recorded for 2.5sec during AF using a roving 20-pole circular catheter in the LA. Reentrant activation was defined as sequential temporal activation of bipoles around the circular catheter. Bipolar EGM fractionation index (FI) and bipolar voltage were used to define CFAEs (FI&gt;7) and low voltage areas (&lt;0.1 mV), respectively. Results: In 21 (66%) patients, 47 reentrant sites were identified. Few (9%) lasted 2.5sec (CL 183±6ms) (Figure, panel A and C), while the majority (91%) were nonsustained (duration 610±288ms, CL 149±11ms) (Figure, panel B and D). Reentrant sites were most common in the PV antrum (71%) and posterior LA (25%). CFAEs were recorded from 18±12% of LA area and most (92±7%) were not associated with reentrant sites. However, 85% of reentrant sites contained CFAEs (Figure, Panel B and D). Very low voltage (&lt;0.1mV) areas comprised 12±10% of LA area and were present in 23% of reentrant sites. Conclusions: In patients with predominantly persistent AF, localized reentrant activation is commonly present, but tends to be transient (&lt;1 second). Although most CFAEs do not co-localize with reentrant sites, the high prevalence of CFAEs and very low voltages within the circuit may indicate slow conduction in diseased myocardium that is necessary for sustaining reentry.
Abstract 16491: Normobaric Hypoxic Training Leads to Improved Exercise Performance, Muscle Strength and Quality of Life in Stable Heart Failure Patients
Authors: Vivek Bhatia, Auris Browne, Carlyn Tan, Julia Shin, Simon Maybaum
Journal: Circulation (2011)

Background: Exposure to altitude leads to beneficial physiological changes that improve oxygen delivery to the periphery. Athletes have utilized simulated altitude enclosures (normobaric hypoxia) a...
Betel quid chewing habit in head and neck cancer patients in 2012-2015, Toungoo, Myanmar.
Authors: Khin Khin Nwe, Soe Aung, Ngwe Sein, Thazin Win
Journal: Journal of Clinical Oncology (2016)

e13040 Background: According to estimated data of cancer registry 2014, head & neck cancer is the most common cancer in Mandalay and third in Yangon, Myanmar. In our country, many people practice betel quid chewing and keeping it in their mouth for long hours. It contains areca nut, tobacco, slaked lime and many other ingredients wrapped in betel leaf. Betel chewing seems to be more prevalent in rural than urban area. We try to find out the prevalence of betel quid chewing in head & neck cancer patients in Toungoo district ,Myanmar. According to Toungoo district health department, urban to rural ratio is 1:2.4 in total population of (242,631) in 2015. Methods: A retrospective, hospital based study of head & neck cancer patients and betel quid chewing was undertaken in Toungoo district, Myanmar. Results: Total (784) cancer patients attended 200-bedded Toungoo General Hospital in 2012-2015. Among them 153 patients (19.51 %) were head & neck cancer patients with a mean age of 59.85 years (range 18 to 78). Male to female ratio is 1.5:1. Regarding staging, 8 patients (5.22%) were stage I, 51 patients (33.33%) stage II, 71 patients (46.4%) stage III, and 23 patients (15.03%) stage IV. Squamous cell carcinoma was the most common histology 146 cases (95.42%). The two common sites were oral cavity 51 patients (33.3%) and larynx 38 patients (27.4%). Buccal mucosa (49%) was the most common site in oral cavity. Betel quid chewing habit was seen in 81.69% of total head and neck cancer patients. The majority (79.2%) of oral cancer patients had history of habitual betel quid chewing and keeping it in buccal cavity even during sleeping hours. In most cases, they started this habit at their teenage and found it very difficult to quit until they came across sinister health consequences. Conclusions: According to these data, betel quid chewing was found to be an extremely prevalent risk factor for head and neck cancer patients in Toungoo district, Myanmar. We need to give health education to avoid betel quid chewing among our community.
The 2016 Li-Fraumeni syndrome cancer spectrum.
Authors: Olivier Caron, Thierry Frébourg, Patrick R. Benusiglio, Laurence Faivre, Catherine Dugast, Valérie Bonadona, Isabelle Coupier, Christine M Maugard, Pascal Pujol, Emmanuelle Barouk-Simonet, Capucine Delnatte, Yves-Jean Bignon, François Eisinger, Nathalie Chabbert-Buffet, Sandra Canale, Leonor Fasse, Stephanie Foulon, Laurence Brugieres
Journal: Journal of Clinical Oncology (2016)

1535 Background: Li Fraumeni syndrome (LFS) is a rare cancer predisposition caused by TP53germline mutation. Its broad cancer spectrum includes breast, sarcoma, brain tumor and leukemia, typically occurring in childhood or young adulthood. The challenge of the LFS clinical management is made even more complex by the suspicion of a much broader spectrum. Methods: The LIFSCREEN French study is an open, randomized, multicentric prospective trial, designed to assess whole body MRI performance. It will evaluate the efficacy and tolerability of 2 screening schemes, performed yearly at least 3 times. At each round, quality of life (QOL) and psychological impact (PI) is assessed. To better define the tumor spectrum, we report here data of the LIFSCREEN participants (pts) and their families, collected at inclusion. Moreover, we describe the cancers identified to date. Results: Any TP53 germline mutation carrier, with or without personal cancer history, aged > 5 and < 71, were included from Oct-2011 to Jan-2015 in 18 participating centers. 101 pts from 75 different families, including 17 children < 18, were enrolled and realized at least one round of screening. All details on the pts and their family, QOL and PI will be described. Since 2011, 19 new primary cancers have been diagnosed in 17 patients (age range in brackets): 4 breast cancers [27-37], 4 brain tumors [6-40], 2 sarcomas [34-43], 2 adenocarcinomas of the lung in 2 never smokers [39-42], 1 pancreatic cancer at 46, 1 kidney at 50, 1 bladder at 45, 1 myeloma at 70, 2 acute myeloid leukemias [50-62], 1 choriocarcinoma at 30, and 2 metachronous colon cancer at 35. Cancer occurrence was not influenced by personal cancer history. 3 cancers were diagnosed in children (brain tumors at 6, 9 and 14). No other cancer in any included family has been reported prospectively. Conclusions: To our knowledge, this is the largest prospective cohort ever described for the LFS. The primary endpoint of the study (efficiency of the WBI) will be assessed in 2018. Nevertheless, our observations seem surprising, with some unexpected off-typical spectrum cancers, a low number of sarcoma, and a global later than awaited cancer occurrence. We would like to share now our preliminary data, as it already sheds a new light on LFS spectrum. Clinical trial information: NCT01464086.
Identification of Caspase-14 as one of the new therapeutic targets for triple negative breast cancer patients using shRNA library and next generation sequence.
Authors: Takehiko Yokobori, Tadashi Handa, Reika Kawabata, Arito Yamane, Shinji Yoshiyama, Ayaka Katayama, Susumu Rokudai, Tetsunari Oyama, Masahiko Nishiyama
Journal: Journal of Clinical Oncology (2016)

e12547 Background: Identification of new therapeutic targets in triple negative breast cancer (TNBC) is needed and challenging. We searched TNBC specifically expressing candidates for target therapy using TNBC cell lines with NGS and shRNA library. The purpose of this study was to identify the new therapeutic target using NGS, and to clarify the expression significance of the candidate in clinical TNBC samples. Methods: We evaluated the high expressing genes in MDA-MB-468, HCC1143 and HCC70 as basal-likeTNBC cell lines compared to the MCF7, BT-474 and T-47D as non-TNBC cell lines using RNA sequencing by NextSeq series. Among these genes, we searched the candidates for target therapy using public expression microarray databases and shRNA library. The expression significance of the gene expression was examined in clinical breast cancer patients using immunohistochemistry. Results: From the initial analysis to identify the TNBC specifically expressing genes, 171 genes were detected as the targets expressing higher in TNBC cell lines than non-TNBC. Then 13 genes were picked up as candidates not expressing in non-cancerous tissues using the database. We further examined the shRNA library-transfected TNBC cell lines using RNA sequencing to identify the TNBC targeting shRNA sequence. As a result, Caspase-14 (CASP14) was characterized as one of the TNBC specific target genes which is not expressing in non-cancerous tissues and can induce cell death against TNBC cells. Expression of CASP14 was localized to the cytoplasm in the cancer tissues. CASP14 staining was stronger in breast cancer tissues, especially TNBC, than in the normal . One hundred nine (44%) breast cancer specimens were assigned to the high CASP14 expression group and 139 (56%) to the low CASP14 expression group; the expression of CASP14 in TNBC type was higher than that of other subtypes. The high CASP14 expression was associated with high Ki-67 expression, low hormone receptor expression, and the high expression of EGFR. Conclusions: These findings suggested that CASP14 targeting strategy might be a potential therapeutic tool against refractory TNBC.
The Effects of an Internet-Based Imagery Rehearsal Intervention: A Randomized Controlled Trial
Authors: Annika Gieselmann, Max Böckermann, Marjolijn Sorbi, Reinhard Pietrowsky
Journal: Psychotherapy and Psychosomatics (2017)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Nightmares are extremely dysphoric dreams, which are prevalent and associated with psychological strain. This study investigated (a) the efficacy of an internet-based imagery rehearsal therapy (IRT), (b) the role of imagery rescription, and (c) the role of guidance during internet-based IRT. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A total of 127 patients suffering from mainly idiopathic nightmares were randomly assigned to 1 of 2 IRT internet-based groups (guided IRT; unguided IRT) or to 1 of 2 active control groups (frequency control group; narrative control group). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; IRT was more effective than a nightmare frequency control condition with respect to nightmare frequency and nightmare distress. Compared to the narrative control group, IRT was only superior in improving nightmare distress but not in nightmare frequency because the narrative control group also improved regarding nightmare frequency. Guidance by a nightmare coach did not affect efficacy, compliance, or dropout. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Internet-based IRT seems to be an effective treatment even when offered with minimal guidance by a nightmare coach. Describing the nightmare narrative in detail already decreased nightmare frequency. However, with regard to inducing decreases in nightmare frequency and nightmare distress, IRT was superior to the narrative control group. The results are discussed with reference to the mastery hypothesis.
Decision support for family history intake to determine eligibility for <i>BRCA</i> testing among multiethnic women.
Authors: Julia E. McGuinness, Meghna S. Trivedi, Alejandro Vanegas, Hilary Colbeth, Rossy Sandoval, Rita Kukafka, Katherine D. Crew
Journal: Journal of Clinical Oncology (2017)

1586 Background: The U.S. Preventive Services Task Force (USPSTF) recommends that women who meet family history criteria for hereditary breast and ovarian cancer (HBOC) be referred for genetic counseling. However, HBOC genetic testing is under-utilized, particularly among racial/ethnic minorities. We evaluated different methods of family history intake, including a validated family history screener, documentation in the electronic health record (EHR), and a web-based decision aid (DA). Methods: Among women undergoing screening mammography, we administered a validated family history screener to determine eligibility for BRCA genetic testing based upon USPSTF guidelines. We developed a patient-centered DA ( RealRisks) which includes modules on breast cancer risk, collection of detailed family history, and information on HBOC genetic testing. Women who met high-risk criteria for breast cancer were enrolled in an intervention trial to determine whether exposure to RealRisks increases referrals for high-risk consultations. BRCA genetic counseling/testing uptake was assessed by self-report and EHR review. Results: From November 2014 to June 2016, 3077 women completed the family history screener. Median age was 59 years (range, 29-99), including 76% Hispanic, 4% Ashkenazi Jewish, and 60% with a high school education or less. 12% met family history criteria for BRCA genetic testing based upon the family history screener, of which only 5.9% had previously undergone genetic counseling or testing. Sixty high-risk women were enrolled to access RealRisks. When family histories based upon the screener, DA, and EHR were compared, 12 (20%) had discrepancies in number of affected relatives, type of cancer, and age at diagnosis which changed eligibility for BRCA testing. Follow-up is ongoing to determine whether the DA facilitates appropriate referrals for genetic counseling. Conclusions: In a population of predominantly Hispanic and less educated women, a large proportion met USPSTF family history criteria for BRCA testing, but uptake of genetic counseling was low. Developing decision support for accurate family history intake is critical to identifying appropriate candidates for genetic referrals.