tbuckley/cabot-search huggingface dataset:
Association of high-throughput RNAi and drug screening with candidate novel therapeutic targets in esophageal carcinoma.
Authors: Irene Yu-Shing Chong, Sean D. Hooper, David Cunningham, Richard Elliott, Lina Chen, James Campbell, Ilirjana Bajrami, Iwanka Kozarewa, Daniel Wetterskog, Paul M. Wilkerson, Maryou B. Lambros, Sheela Rao, Naureen Starling, Ian Chau, Christopher J. Lord, Alan Ashworth
Journal: Journal of Clinical Oncology (2013)

31 Background: Oesophageal cancer is the sixth most commonly diagnosed cancer worldwide and carries a poor prognosis. Targeted therapeutic strategies have relied on the identification of genes which are amplified and overexpressed but the discrimination between genes which drive cancer and those that are coincidental has not yet been fully achieved. Methods: We carried out a functional genetic screen of 714 kinases in 18 tumour cell line models of oesophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC) to identify genes critical to the survival of specific oesophageal subtypes. High throughput drug screening of 80 compounds, largely comprising those used in clinical trials or in routine clinical practice, was undertaken in parallel to reveal druggable targets and to validate functional screening results. Results: We show proof of principle that the integration of functional and drug profiling results with molecular profiling data is a valid approach for identifying druggable targets by correlating the effects of ERBB2, EGFR and CDK6 gene knockdown with sensitivity to drugs targeting their respective proteins. We have characterised new genetic dependencies for EAC involving TGF beta signalling and the JAK/STAT pathway. Decreased cell viability associated with silencing of ACVR2 and ACVR1C (activin receptors involved in TGF beta signalling) was consistent with sensitivity to nilotinib, a cABL inhibitor that modulates TGF beta signalling. Furthermore, decreased cell viability in EAC models was observed with silencing of JAK2. This strongly correlated with sensitivity to PF-04691502 and BEZ 235, both potent inhibitors of PI3K/mTOR which signal downstream of JAK2. We have validated novel sensitivity to small molecule tankyrase inhibitors in a subgroup of oesophageal models, suggesting that a subset of Wnt dependent oesophageal cancers could be targeted with these agents. Conclusions: The molecular and functional genetics of oesophageal cancer is poorly understood. By generating functional viability and drug sensitivity data for a panel of oesophageal tumour cell lines, we have identified new genetic dependencies and candidate drug targets for this aggressive disease.
Clinical characteristics and management of late symptom flare following stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Jennifer Ai-Lian Woo, Leonard N. Chen, Eric Oermann, Viola Chen, Thomas M. Yung, Joy S. Kim, Brian Timothy Collins, Simeng Suy, John H. Lynch, Anatoly Dritschilo, Sean P. Collins
Journal: Journal of Clinical Oncology (2014)

194 Background: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. While acute urinary symptoms are well recognized, late toxicities of SBRT have not been fully described. Here, we characterize the clinical features of late symptom flare and describe symptom management approaches. Methods: Two hudred sixteen patients with clinically localized prostate cancer were treated with SBRT between February 2008 and January 2011 at Georgetown University Hospital. Twenty-nine patients who experienced late-symptom flare were included in this retrospective analysis. Treatment was delivered using the CyberKnife (35 Gy to 36.25 Gy in five fractions). Prevalence of urinary toxicities was determined using CTCAE v.4. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite (EPIC) short form. Results: Median age was 66 with 55% being of African descent. Late grade 2 frequency/urgency peaked at 12 months (17.2%), then returned to baseline at 18 months. Late grade 2 retention peaked at 18 months (65.5%), then returned to baseline at 24 months. Late grade greater than or equal to 1 dysuria peaked at nine months (25.0%), then returned to baseline at 24 months. Alpha-antagonist usage peaked at 18 months (85%) then decreased at 24 months. At 12 months, 21% required anti-inflammatories and/or urethral analgesics. Median AUA score rose from a baseline of 6 to 15 at 12 months, then returned to baseline by 24 months. EPIC urinary function and bother scores dropped to a nadir at 9 to 12 months post-treatment, then returned to baseline at 24 months. Conclusions: Symptom flare is a late syndrome consisting of various degrees of urinary frequency/urgency, retention and dysuria. It occurs approximately one year following SBRT, resolves spontaneously, and urinary function returns to baseline by two years. Early identification and initiation of conservative symptomatic management may decrease the need for invasive interventions. Anticipatory counseling prior to treatment may limit bother due to these transient urinary symptoms.
Clinical benefits TH-302, a tumor-selective, hypoxia-activated prodrug, and gemcitabine in first-line pancreatic cancer (PanC).
Authors: M. J. Borad, E. G. Chiorean, J. R. Molina, A. C. Mita, J. R. Infante, W. R. Schelman, A. M. Traynor, G. Vlahovic, D. S. Mendelson, S. G. Reddy
Journal: Journal of Clinical Oncology (2011)

265 Background: Gemcitabine (G) is the standard treatment for first- line PanC. PanC is one of the most hypoxic solid tumors. TH-302 is an inert prodrug of brominated isophosphoramide mustard and undergoes selective activation in deep hypoxia. As a single agent, tumor responses were reported in patients (pts) with metastatic melanoma, SCLC, and head/neck cancer at TH-302 weekly doses of 480-575 mg/m 2 . Methods: Eligible pts for the PanC expansion of this phase I/II study ( NCT00743379 ) had ECOG &lt;1, locally advanced or metastatic PanC previously untreated with systemic chemotherapy other than adjuvant G, 5FU, and/or radiation. IV TH-302 was dosed at 240-575 mg/m 2 (240 or 340 in expansion) with standard dose G (1000 mg/m 2 ) on days 1, 8 and 15 of a 28-day cycle. Serum protein and microRNA hypoxia biomarkers were analyzed at baseline, start of cycle 3 and end of study. Results: 46 PanC subjects (12 locally advanced, 34 distant mets); median age: 63 (range 41-83); 24 male; ECOG 0/1 in 29/17 pts; RECIST response rate (RR) of 21%, median PFS of 6.1 mo (95%CI 4.8, 7.7) and median survival of 11.4 mo (95%CI 6.0, not reached) were observed. RR was 23% with median survival of 7.4 mo in pts with distant mets. 52% of pts had a &gt;50% decrease in CA19-9. Common adverse events were skin or mucosal toxicity, nausea, fatigue and vomiting; most grade 1/2. Grade 3/4 neutropenia, thrombocytopenia and anemia in 68%, 64%, and 20% of pts respectively. The dose intensities at 240 mg/m 2 and 340 mg/m 2 were similar and related to hematologic toxicities. Skin toxicities were less common at 240 mg/m 2 . A TH-302 dose response was present with higher RR and PFS at 340 mg/m 2 . Initial serum hypoxia biomarkers did not identify a preferential pt population. Conclusions: The activity and clinical benefits of the combination of TH-302 with G in first line PanC are promising as compared to previous studies of G alone. TH-302 adds to the hematologic toxicity of G, but the regimen is well tolerated. The safety and activity provided rationale for comparing TH-302 plus G versus G alone in a randomized phase II trial ( NCT01144455 ) and indicate TH-302 may complement G by penetrating into the hypoxic regions of the PanC tumors where activation induces cytotoxicity. No significant financial relationships to disclose.
Association between polymorphisms of the FOXF1 and MHC locus genes and gastroesophageal reflux disease (GERD).
Authors: Wei Fan Liu, Christine Lam, Ryan Del Bel, Kevin Chan, Linda Miller, M Catherine Brown, Zhuo Chen, Dangxiao Cheng, Devalben Patel, Wei Xu, Gail Elizabeth Darling, Geoffrey Liu
Journal: Journal of Clinical Oncology (2014)

15 Background: GERD predisposes to Barrett’s Esophagus (BE), a precursor lesion to esophageal adenocarcinoma (EA). Recently a large genome-wide association study found two germline markers to be associated with BE, FOXF1 rs9936833 (C Allele) and MHC rs9257809 (A allele). An additional study linked FOXF1 rs9936833 to EA. We assessed whether these same polymorphisms are associated with GERD. Methods: Patients with reflux symptoms referred for esophageal manometry/24-hr pH monitoring at University Health Network (Toronto) were enrolled. DNA extracted from blood was genotyped using a Taqman PCR assay. GERD cases were defined as having DeMeester scores of ≥14.7 or prior evidence of reflux esophagitis on endoscopy. DeMeester &lt; 14.7 defined controls. Logistic regression analysis, adjusted for clinical risk factors, was used to calculate odds ratios (95% confidence intervals) for each polymorphism relative to GERD. Results: Of 182 patients, the median age was 50 years, 62% were female and, 52% met the definition for GERD. Males, higher BMI, alcohol consumption, FOXF1, and MHC polymorphisms were each individually associated with GERD. In the multivariate analysis, after adjusting for gender and BMI, FOXF1 rs9936833 remained significant, with an aOR of 1.82 (95%CI: 1.1-3.0; p=0.02) for an increase in each C allele. MHC rs9257809 also remained significant, with an aOR of 9.36 (2.9-30; p&lt;0.001) comparing AA to AG (there were no patients with GG). When both polymorphisms were placed in the same model, the aORs were 2.10 (1.2-3.5; p=0.006) and 11.0 (3.3-36; p&lt;0.001), per increase in each risk allele, respectively. Conclusions: There are strong, significant associations for increased GERD risk by the C allele in FOXF1 rs9936833 and the A allele in MHC rs9257809 among patients complaining of reflux symptoms. FOXF1 is associated with development of gastrointestinal smooth muscle, possibly contributing to the contractibility of the gastroesophageal junction. The MHC polymorphism is in linkage disequilibrium with HLA alleles involved in T-cell regulation, suggesting the possibility of T-cell involvement in reflux esophagitis. WFL and CL are co-first authors. GL and GED are co-senior authors.
Safety analysis of the French Intergroup R98 trial comparing 5FU-leucovorin alone or with irinotecan in resected stages II-III rectal cancers
Authors: P. Piedbois, M. Ychou, A. Zawadi, J. Douillard, V. Guérin-Meyer, T. André, O. Dupuis, P. Rougier, R. Faroux, E. Quinaux
Journal: Journal of Clinical Oncology (2008)

4088 Background: Irinotecan combined with 5FU/LV improves the outcome of patients (pts) with advanced colorectal cancer. R98 trial tests the hypothesis that this combination is superior to 5FU/LV alone to prevent recurrence or death in resected stages II-III rectal cancers. Methods: Between 03/1999 and 12/2005, 357 pts were postoperatively randomized to 5FU/LV (control arm) or 5FU/LV + irinotecan. Primary endpoint was DFS. The control arm consisted of either a Mayo-Clinic regimen (A: LV 20 mg/m², 5FU 425 mg/m² bolus days 1–5, repeated at d29, d57, d92, d127 and d162) or a LV5FU2 regimen (A’: LV 200 mg/m² over 2-hour, 5FU 400 mg/m² bolus and 600 mg/m² 22-hour infusion, d1–2, Q2W for 12 cycles), depending on centre choice. Experimental arm (B) consisted of LV5FU2 + irinotecan 180 mg/m² d1 of every cycle. Results: We present here the final safety analysis based on 341 evaluable pts. 172 pts were treated in the control arm (A, 56 pts or A’,116 pts), and 169 pts in the experimental arm (B). Pretreatment characteristics were well balanced between the groups; median age 62 years, stage II in 32% of pts. 68% of pts received preoperative RT, and 80% had sphincter conservation. 95% arm A and A’, and 72% arm B pts received more than 75% of planned chemotherapy dose. No toxic death was reported. G3–4 toxicity per pt was as follows for arms A, A’, and B: neutropenia 36%, 6%, 33%; diarrhea 9%, 9%, 13%; nausea-vomiting 2%, 1%, 7%; mucositis: 5%, 0%, 1%; infection: 7%, 2%, 1%; any toxicity (except alopecia): 50%, 20%, 47%; other G3–4 toxicities <5%. G3- 4 neutropenia and vomiting were significantly higher in the experimental arm than in the control arm (33% vs 16%; P<0.0001 and 5% vs 0%; p=0.002, respectively). RT was not associated with a statistically significant increase risk of diarrhea. Conclusions: The addition of irinotecan to a LV5FU2 regimen led to a decrease of dose intensity, and to an increase of neutropenia and of vomiting in the adjuvant treatment of rectal cancer. The safety profile of 5FU/LV + irinotecan remained however acceptable compared to 5FU/LV alone. First efficacy analysis is expected at the end of 2008. Study supported by Pfizer, France Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Roche Baxter, Merck, Pfizer, sanofi-aventis Pfizer, sanofi-aventis
Nasopharyngeal carcinoma treated by intensity-modulated radiotherapy: CAMS experience
Authors: J. Yi, L. Gao, X. Huang, J. Luo
Journal: Journal of Clinical Oncology (2008)

17029 Background: To report the preliminary results of nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy (IMRT) Methods: Between November 2001 and March 2006, 147 newly diagnosed NPC patients were treated by IMRT. The diseases were in stage I 3, stage II 33, stage III 67 and stage IV 44. The prescribed doses were 70 Gy and 74–78Gy to the gross tumor volume for T1/2 and T3/4 patients irrespectively; 70 Gy to all positive lymph nodes; 60Gy to the clinical target volume 1, and 50–56 Gy to the clinically negative neck and supraclavicular region. Local control(LC), overall survival(OS), disease-free survival (DFS) and distant metastasis- free survival (DMFS) were estimated using the Kaplan-Meier method. Normal tissue toxicities were evaluated by RTOG criteria. Results: The 3-year LC, OS,DFS and DMFS of whole group were 93.5%,93.2%,72.6% and 74.4%. N stage was the predictive factor for OS, DFS and DMFS under univariate analysis; there was no independent prognosis factor was found under multivariate analysis. The incidence of Grade1, 2 and 3 acute toxicities of parotid were 40.1%, 56.5% and 1.4%, irrespectively. The proportion of patients with Grade 2 xerostomia were 43%,4.9% and 3.2% at 3months, 1 year and 2years, irrespectively. Distant metastases were found in 19patinets (12.9%). Conclusions: Our data show that nasopharyngeal carcinoma treated by IMRT according to our target definition and dose prescription reached a high rate of local regional control, with a mild acute and late toxicities. The distant metastasis is a major failure pattern. No significant financial relationships to disclose.
Effect of HLA-Matching on Outcome of Hematopoietic Stem Cell Transplantation from Unrelated Donors: A IBMDR-GITMO Study.
Authors: Roberto Crocchiolo, Fabio Ciceri, Rosa Oneto, Barbara Bruno, Simona Pollichieni, Nicoletta Sacchi, Maria Pia Sormani, Renato Fanin, Giuseppe Bandini, Alberto Bosi, Alessandro Rambaldi, Paolo Emilio Alessandrino, Michele Falda, Andrea Bacigalupo
Journal: Blood (2007)
Primary study on target reproducibility of peripheral non-small cell lung cancer in cone-beam CT based image-guided radiotherapy
Authors: Z. Ying-jie, J. B. Li, J. M. Yu, J. Xing, M. Xu
Journal: Journal of Clinical Oncology (2008)

7596 Background: To evaluate impact of the change of position, volume and shape of the targets of peripheral non-small cell lung cancer (NSCLC) on the target reproducibility, analyze PTV margins and guide the modification of the treatment planning. Methods: Ten patients with peripheral NSCLC treated with 3D-CRT were scanned by KV CBCT per week until treatment planning changed and 3∼5 sets of CBCT image for per patient were got. Set-up errors were corrected on-line by registration of the CBCT images and planning CT images and the CBCT image sets were transferred to the TPS. In the TPS, CBCT images and CT images were registered off-line, and the volumes of the primary tumor were delineated on the CBCT images registered to CT images, which were denominated as CTCT-IGTV consisted of GTV plus IM to analyze the change of position, volume and shape of the targets. A group margin was got by means of the formula (M=2.0Σ+0.7σ) which was proposed by Stroom. Through DVH, the volume percent of CTCT-IGTVs irradiated with 95% prescribed dose were compared with that of CT-PTV, so as to judge whether part of CTCT-IGTVs not be irradiated in some weeks. Characterized PTV margin was got by increasing the margin to CT-GTV inch by inch until the volume percent of CTCT-IGTVs irradiated with 95% prescribed dose less than that of characterized PTV. Results: The group margin due to targets displacement in different fraction of radiotherapy was 0.80cm, 0.96cm, and 0.87cm on X,Y,Z axis respectively. Volume of the targets significantly decreased at the third week (39.7±29.1 cm3) compared to that at the first (51.1±33.9cm3) (P=0.006) and second week (48.6±34.0 cm3) (P=0.013) during radiotherapy. When PTV margins were prescribed as 8∼10mm, three targets (3/41 weeks) were not irradiated perfectly. Characterized PTV margins were 4∼11mm which were not significantly different from that 8∼10mm prescribed for treatment planning (P>0.05), but the variations for individual patient were greater. Conclusions: Target displacement and volume enlargement is the major reason to result in leakage of irradiation to part of the target, image-guided radiotherapy can monitor and evaluate target repetitiveness during radiotherapy to guide modification of the treatment planning of NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Li Jianbin
Asking older people two simple questions accurately detects depression risk, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Two simple questions can diagnose depression in older people as effectively as more complex screening tools, a review of clinical studies has found.1

Depression is common in older people, with a prevalence of 10-20%. As well as reducing functioning and quality of life, it is associated with increased use of health services. Early detection and treatment can improve prognosis, but screening for depression in older people is more difficult than in younger age groups because many of the somatic …
Preliminary evaluation of radioimmunotherapy with an <sup>131</sup>I labelled small immunoprotein targeted against the extra domain B of fibronectin in combination with whole brain radiation therapy in patients with multiple brain metastases from solid tumors.
Authors: S. Lastoria, L. D'Ambrosio, M. Aurilio, R. Marreno, L. Giovannoni, H. D. Menssen, D. Neri, A. Shah, F. Di Gennaro, C. Caraco, B. Pecori, L. Aloj
Journal: Journal of Clinical Oncology (2011)

e12502 Background: The extradomain B (ED-B) of fibronectin (FN) is a highly expressed marker of tumor angiogenesis and thus provides a molecular target for radioimmunotherapy (RIT). The RIT agent 131I-L19SIP is a small immunoprotein (SIP) labeled with I-131 recognizing the ED-B domain. Previous phase I/II 131I-L19SIP RIT studies have have shown efficacy in a variety of cancer types. We are now evaluating uptake of 131I-L19SIP in brain metastases, the safety of combined RIT and whole brain radiation therapy (WBRT) and efficacy. Methods: Ten patients (7 M, 3 F, 40-72 yo, 3 melanoma, 1 breast, 4 lung and 2 colorectal cancer) with brain metastases not amenable to local treatment, were enrolled (October 2009 - November 2010). Workup included whole body FDG-PET and contrast enhanced MRI and/or CT. All patients underwent WBRT (30 Gy). ImmunoPET with I-124 labeled L19SIP was performed in 9/10 patients (one had 131I-L19-SIP SPECT) to measure uptake in target lesions. Lesion uptake >4 times higher than contra-lateral normal brain was required for eligibility for 131I-L19SIP therapy (4.1 GBq/m2). 131I-L19SIP was administered within 3 weeks from completion of WBRT. No other treatment was given from 6 weeks prior to enrollment and until first assessment (5.3 ± 1.3 weeks after treatment). Results: Six patients were treated with 131I-L19SIP (6740 ± 347 MBq), 1 was ineligible for low lesion uptake, and 3 were excluded for rapidly progressing systemic disease. The estimated dose boost delivered to brain lesions ranged from 3.4 to 25.4 Gy. One patient developed grade 4 neutropenia requiring hospitalization. All other hematologic toxicity (grade 3 or lower) required no further action. The first assessment evaluation showed a partial response in 2 patients, disease stabilization in 2 patients, and progressive disease in 2 patients. Conclusions: In this patient population with very poor prognosis the application of 131I-L19SIP in addition to WBRT is feasible, well tolerated and provides acceptable levels of toxicity. Further studies are needed to assess the therapeutic efficacy of this approach.
Assessing the true nature of unplanned cancer care.
Authors: Suzanne Tamang, Manali I. Patel, Sam Finlayson, Xuemei Chen, Julie Lawrence Kuznetsov, Douglas W. Blayney, Nigam Shah
Journal: Journal of Clinical Oncology (2014)

183 Background: Unplanned care can result in poor outcomes that are potentially preventable. The design of effective interventions to improve outcomes for cancer patients requires a better understanding of the true nature of unplanned care. Although cancer care teams document each patient’s care trajectory in detailed free-text notes, care outcomes are typically measured from structured patient record data and do not contain key information necessary for quality improvement efforts, such as the etiology of emergent events, or events that occur at outside facilities. To inform clinical effectiveness work at Stanford’s Cancer Institute, we describe our application of text-mining to improve the assessment of post-diagnosis morbidity outcomes. Methods: We conducted a retrospective study of unplanned care among 3,318 patients with a new diagnosis of breast, gastrointestinal, or thoracic cancer during 2010-13. Using a validated framework for clinical text-mining, we analyzed 308,000 notes for two tasks. First, we extract information on external unplanned events that are documented by providers. Second, we profile symptom mentions in Emergency Department (ED) notes. Results: For all cancer patients, text-mining detected over 400 unplanned events (93% PPV) at outside facilities, resulting in patient rates of 5% in the first 30 days, and 11% up to one year post-diagnosis. Among breast cancer patients, the top three symptoms reported in ED notes are pain (89%), nausea (37%) and fever (18%). Pain is consistently the most prevalent symptom up to one year after diagnosis, other symptoms exhibit more dynamic trends; wound related disorders and nausea are more prevalent among ED admissions in the first three months, whereas fever, cognitive impairment and mental health issues become more prevalent among admissions after the first three months of cancer care. Conclusions: The application of text-mining methods can improve the quantification of morbidity outcomes by improving the estimation of unplanned care rates and by providing continued learning for symptom-driven interventions to mitigate preventable emergent care. Although additional information gaps in care trajectories may continue to exist, text-mining can aid in assessing the true nature of unplanned care.
Effects of Aprepitant on Drug Metabolism in Lymphoma Patients Receiving Multi-Day Chemotherapy Regimen of Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, + Rituxan (R/CHOP): Randomized, Cross-Over Study
Authors: Saroj Vadhan-Raj, Ivan Spasojevic, Xiao Zhou, Jorge E Romaguera, Michelle A. Fanale, Luis E Fayad, Nathan H. Fowler, Auris Huen, F.B. Hagemeister, Maria Alma Rodriguez, Sattva S. Neelapu, Felipe Samaniego, Anas Younes, Larry W Kwak
Journal: Blood (2011)