tbuckley/cabot-search huggingface dataset:
Contents Vol. 77, 2008
Authors: C. Franco, A. Martínez-Aran, J. Sánchez-Moreno, M. Reinares, M. Salamero, C. Arango, J.L. Ayuso-Mateos, F. Kapczinski, E. Vieta, Laura Sirri, Silvana Grandi, Giovanni A. Fava, John S. Ogrodniczuk, Anthony S. Joyce, Larry D. Lynd, William E. Piper, Paul I. Steinberg, Kathryn Richardson, Dionyssios Leftheriotis, Ioannis Michopoulos, Panayota Flevari, Athanassios Douzenis, Christoforos Koborozos, Anna Kostopoulou, George N. Theodorakis, Lefteris Lykouras, Dimitrios T. Kremastinos, Franziska Geiser, Christian Meier, Ingo Wegener, Katrin Imbierowicz, Rupert Conrad, Reinhard Liedtke, Johannes Oldenburg, Ursula Harbrecht, Robert H. Howland, Pamela J. Schettler, Mark Hyman Rapaport, David Mischoulon, Trisha Schneider, Amy Fasiczka, Katia Delrahiem, Rachel Maddux, Michael Lightfoot, Andrew A. Nierenberg, A.R. Rosa, Eriko Nakatani, Akiko Nakagawa, Gerda van Aalst, Robert A. Schoevers, Jaap Peen, Ernesto Caffo, Carlotta Belaise, Barbara Forresi, Jouko K. Salminen, Hasse Karlsson, Jarmo Hietala, Jaana Kajander, Sargo Aalto, Juha Markkula, Helena Rasi-Hakala, Tuula Toikka, Henricus L. Van, Jack Dekker
Journal: Psychotherapy and Psychosomatics (2008)
Clinical characteristics of patients with malignant pleural mesothelioma (MPM) harboring somatic BAP1 mutations.
Authors: Marjorie Glass Zauderer, Matthew Joseph Bott, Robert McMillan, Camelia S. Sima, Valerie W. Rusch, Lee M. Krug, Marc Ladanyi
Journal: Journal of Clinical Oncology (2012)

1541 Background: Efforts to elucidate tumorigenic mutations in MPM are essential to advance therapy. We reported a 23% incidence of somatic mutations in BRCA1-associated protein-1 (BAP1) in 53 patients with MPM (Bott et al. Nat Genet 2011). Germline BAP1 mutations were also reported in two families with a predisposition to mesothelioma and uveal melanoma (Testa et al. Nat Genet 2011). While BAP1 somatic mutations are more common in poor prognosis uveal melanoma (84% class 2, 4% class 1; Harbour et al. Science 2010), the significance of these mutations in MPM is unknown. Therefore, we analyzed the clinical characteristics of patients with somatic BAP1 mutations in order to describe this newly identified subpopulation. Methods: We reviewed the charts of 121 patients with tumors tested for somatic BAP1 mutations. Results: Patient characteristics are in the Table. Twenty percent harbored somatic BAP1 mutations. Other than the percent of current or former smokers (75% BAP1 mutations, 42% BAP1 wild-type, p=0.006), no other clinical feature was significantly different among those with and without BAP1 mutations. Among 53 samples analyzed for NF2 mutation and p16 deletion, no correlation was seen with BAP1 mutation. Conclusions: Somatic BAP1 mutations occur in about 20% of MPM tumors. Aside from smoking history, no other differences in clinical characteristics or outcomes were noted in the BAP1 mutated cases. Similar efforts are needed to describe the features of germline mutations in order to define this new cancer predisposition syndrome. We are planning a prospective trial to further evaluate the prevalence of germline BAP1 mutations, and we are also exploring the therapeutic implications. [Table: see text]
The Surge of Opioid Use, Addiction, and Overdoses
Authors: Bertha K. Madras
Journal: JAMA Psychiatry (2017)

Silvia S. Martins, MD, PhD; Aaron Sarvet, MPH; Julian Santaella-Tenorio, MSc; Tulshi Saha, PhD; Bridget F. Grant, PhD; Deborah S. Hasin, PhD
SLC1A5 to predict outcome with chemotherapy in early triple-negative breast cancer.
Authors: Anna Maria Affan, Vinay Varadan, Hannah L. Gilmore, Kristy Miskimen, Young Joo Jeon, Shikha Parsai, Ze'ev Ronai, Lyndsay Harris
Journal: Journal of Clinical Oncology (2015)

2530 Background: TNBC are high grade tumors which have a poor prognosis. SLC1A5 is a neutral amino acid transporter found in these tumors and high levels correlate with aggressive biological behavior. By targeting SLC1A5 function, tumor cell growth can be inhibited and autophagy activated which should result in improved survival benefit for patients with TNBC. We evaluated the role of SLC1A5 on tumor death rate in patients who were treated with chemotherapy for early TNBC. Methods: A retrospective, cohort study of patients with TNBC was performed to evaluate survival compared with the level of expression of SLC1A5. A histogram was constructed to determine a median point which could be used to define a “high” versus “low” score. Five was used as the average cut-point. Thereafter to determine overall survival, Kaplan-Meier product-moment technique (K-M) was used, with comparisons between groups made by using the log rank test. Statistical significance was taken as p < 0.05. Results: The cohort consisted of 171 patients with TNBC. The median age was 51 years with similar distribution between node positive and node negative cases. Survival information was available for 112 patients with data available on the SLC1A5 score. There was a significant association of the outcome of interest, overall survival, with the SLC1A5 score with a worse outcome noted in tumors with higher expression (p = 0.00189). Furthermore, 80 patients with TNBC who received chemotherapy with higher levels of SLC1A5 showed worse survival (p = 0.0005). Additionally, the relationship between SLC1A5 and hypoxia-induced upregulation of Carbonic Anhydrase IX (CAIX), was explored using the Welch Two Sample t-test. There was a significant association with higher levels CAIX associated with higher SLC1A5 (p = 0.0189). Conclusions: This study suggests that SLCA15 is associated with tumor hypoxia and worse outcome in chemotherapy treated patients. The results emphasize the importance of evaluating proteins involved in cell metabolism and autophagy, to aid in the development of novel targets. The relationship of CAIX with SLCA15 implies that the latter may be involved in tumor hypoxia that needs further exploration in additional cohorts and clinical trials.
CXCR4 expression and circulating tumor cell (CTC) counts evaluated as prognostic markers in extensive disease small cell lung cancer (ED-SCLC) patients (pts).
Authors: John R Stille, Amy Flynt, Victoria L Peek, Steven Gross, Jan Keij, Mark Carle Connelly, Kurt Baeten, Oday Hamid, Carrie Morano, Eyas Raddad, Madeline Ivette Repollet, Stephanie Roberson, Renouard Sanders, Suzane L. Um, Sameera R. Wijayawardana, S. Betty Yan
Journal: Journal of Clinical Oncology (2015)

e18558 Background: CXCR4, highly expressed in SCLC, has been implicated in inducing tumor cell migration/invasion and shown to be prognostic of outcome. We evaluated CXCR4 expression in pretreatment CTCs and tumor tissue and post-carboplatin/etoposide (SOC) treatment CTCs in a phase 2 ED-SCLC study of a CXCR4 inhibitor (NCT 01439568). Methods: 89 pts were treated with 42 receiving SOC. CTCs were analyzed using CELLSEARCH CXC kit combined with a PE labelled anti-CXCR4 Ab. CXCR4 expression on CTCs was scored visually by an operator and with specialized software. Baseline tumor CXCR4 expression was quantified (H-score) by immunohistochemistry. Optimum cutoff values for CTC counts and CXCR4 expression on CTCs and tumor were determined from ROC curves. Kaplan Meier curves were used to assess cutoffs as PFS prognostic variables for SOC pts. Results: See Table. For all pts, baseline % CXCR4+CTCs correlated positively with tumor CXCR4 expression (r=0.423; p=0.001). The agreement between operator and software scoring of CXCR4 expression in CTCs was 83%. For the SOC pts, the presence of <6.9% CXCR4+CTCs at baseline was prognostic of better PFS (HR=0.34 [0.13-0.88]; log rank p=0.075), tumor tissue CXCR4 expression was not significant (log rank p=0.675). At C2D1 (Cycle 2 Day 1), <2 CTCs was also prognostic of better PFS (HR=0.19 [0.07-0.54), log rank p=0.004]. In the SOC pts, 83% (30/36) had ≥2 CTCs and 76% (25/33) had ≥6.9% CXCR4+ CTCs at baseline; 41% (11/27) had ≥2 CTCs and 25% (6/24) had ≥6.9% CXCR4+CTCs at C2D1. The mean percent decrease from baseline to C2D1 for CTCs (83%, p<0.001) and %CXCR4+ CTCs (52%, p=0.017) was significant. Conclusions: In ED-SCLC pts, while CXCR4 positivity in tumor was not prognostic in this small study, having either <6.9% CXCR4+ CTCs at baseline or <2 CTCs after 1 cycle of SOC treatment was prognostic of better survival. Clinical trial information: NCT01439568. Tumor CXCR4+ H-score Baseline* CTCs Baseline* %CXCR4+ CTCs C2D1* CTCs C2D1* %CXCR4+ CTCs 89 pts N^ 69 78 70 mean±SD 203±82 656±1662 24±26 median 200 51 18 (range) (5-300) (0-9948) (0 –100) 42 SOC pts N^ 33 36 33 27 24 mean±SD 200±85 702±1927 27±25 25 ± 80 11 ± 20 median 200 99 21 0 0 (range) (5-300) (0-9948) (0–100) (0 - 406) (0 – 67) * /7.5ml ^ pts with evaluable results.
Using CHFR expression to predict response and survival after first line treatment with carboplatin-paclitaxel in NSCLC.
Authors: Rathi Narayana Pillai, Seth Aaron Brodie, Ge Li, James Gordon Herman, Malcolm Brock, Taofeek Kunle Owonikoko, Suresh S. Ramalingam, Fadlo Raja Khuri, Johann Christoph Brandes
Journal: Journal of Clinical Oncology (2012)

10625 Background: The identification of resistance mechanisms for conventional chemotherapy in lung cancer is of fundamental importance not only for personalization of chemotherapy but also for the subsequent development of novel targeted approaches to overcome this resistance. Currently, there is no clinically validated test for the prediction of response to tubulin-targeted agents in NSCLC. Our previous preclinical work identified Checkpoint with Forkhead and Ringfinger domain” (CHFR) as a predictor of taxane cytotoxicity in in vitro models. The current work assessed the translational significance of this finding in a cohort of US veterans treated at a single-institution. Methods: We studied a cohort of patients with advanced NSCLC treated with taxane-containing frontline regimens at the Atlanta VA Medical Center between 2000 and 2009. Archived paraffin-embedded tissue was retrieved and stained for CHFR expression using standard immunohistochemical techniques. Level of protein expression was assessed by light microscopy and scored for intensity of CHFR staining. Intensity of staining was correlated with clinical outcome including objective response and median overall survival using Chi-Square test and Cox proportional models. Results: We analyzed tumor samples from 45 eligible patients with median age 62.6 years, M/F (44/1). In this cohort, high expression of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 54% in patients with CHFR-high vs. only 18% in those with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p=0.02). Median overall survival was strongly correlated with response to first-line therapy (clinical benefit: 9.24 months; PD: 4.7 months; p&lt;0.001) and with CHFR expression status (CHFR low: 10 months; CHFR high: 5.6 months; p =0.01). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.
Cetuximab metastatic colorectal cancer strategy (ERMES) study: A phase III randomized two arm study with FOLFIRI + cetuximab until disease progression compared to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until disease progression in first-line treatment of patients with RAS and BRAF wild type metastatic colorectal cancer.
Authors: Carmine Pinto, Nicola Normanno, Armando Orlandi, Evaristo Maiello, Domenico Bilancia, Domenico C. Corsi, Emiliano Tamburini, Salvatore Pisconti, Francesco Ferraú, Francesco Di Costanzo, Stefania Gori, Bruno Daniele, Giuseppe Tonini, Alberto Zaniboni, Hector Soto-parra, Giovanni Luca Frassinetti, Rosario Vincenz Iaffaioli, M. Giulia Zampino, Lazzaro Repetto, Carlo Antonio Barone
Journal: Journal of Clinical Oncology (2017)

TPS810 Background: The optimal duration and content of first-line therapy in mCRC pts once they have achieved objective response is controversial. In the FIRE-3 trial, ETS was significantly associated with PFS and OS. Based on this evidence it can be hypothesized that once this goal has been achieved, further exposure to combined antineoplastic treatment may not result in improvement or preservation of such result but only in an increase of toxicity. We designed a strategy study to compare FOLFIRI + cetuximab until PD to FOLFIRI + cetuximab for 8 cycles followed by cetuximab alone until PD in first line treatment of RAS/BRAF WT mCRC pts. Methods: This is a multicenter, open-label, randomized phase III trial. Untreated and unresecteble RAS/BRAF WT mCRC pts were randomized 1:1 to receive Cetuximab (400 mg/mq w1 and then 250 mg/mq weekly) + FOLFIRI until PD (standard arm) or Cetuximab (400 mg/mq week 1 and then 250 mg/mq weekly) + FOLFIRI for 8 cycles followed by Cetuximab monotherapy until PD (experimental arm). Tumor assessment is planned every 8 weeks. The objective of the study is to demonstrate a not inferior efficacy and a better toxicity profile for the experimental treatment compared to the standard treatment. The co-primary endpoints are PFS and incidence of G 3-4 AEs. Secondary endpoints are OS, ORR, ETS (8 weeks) and safety. A prospective multiple gene mutation analysis by NGS of both tumor tissue and blood will be performed to find potential predictive factors and surrogate markers of treatment efficacy. The two co-primary endpoints will be compared between the two arms using a fixed-sequence testing procedure to control for the family-wise type I error rate of 0.05 in a strong sense. This sequence considers that a reduction of grade 3-4 AEs is only of relevance, if non-inferiority is shown regarding PFS. 600 evaluable pts will be enrolled and randomized. Study recruitment started on January 2015, currently 139 pts have been randomized. Clinical trial information: NCT02484833.
The antiproliferative ELF2 isoform, ELF2B, induces apoptosis in vitro and perturbs early lymphocytic development in vivo
Authors: Fiona H. X. Guan, Charles G. Bailey, Cynthia Metierre, Patrick O’Young, Dadi Gao, Teh Liane Khoo, Jeff Holst, John E. J. Rasko
Journal: Journal of Hematology & Oncology (2017)

ELF2 (E74-like factor 2) also known as NERF (new Ets-related factor), a member of the Ets family of transcription factors, regulates genes important in B and T cell development, cell cycle progression, and angiogenesis. Conserved ELF2 isoforms, ELF2A, and ELF2B, arising from alternative promoter usage can exert opposing effects on target gene expression. ELF2A activates, whilst ELF2B represses, gene expression, and the balance of expression between these isoforms may be important in maintaining normal cellular function. We compared the function of ELF2 isoforms ELF2A and ELF2B with other ELF subfamily proteins ELF1 and ELF4 in primary and cancer cell lines using proliferation, colony-forming, cell cycle, and apoptosis assays. We further examined the role of ELF2 isoforms in haemopoietic development using a Rag1 -/-murine bone marrow reconstitution model. ELF2B overexpression significantly reduced cell proliferation and clonogenic capacity, minimally disrupted cell cycle kinetics, and induced apoptosis. In contrast, ELF2A overexpression only marginally reduced clonogenic capacity with little effect on proliferation, cell cycle progression, or apoptosis. Deletion of the N-terminal 19 amino acids unique to ELF2B abrogated the antiproliferative and proapoptotic functions of ELF2B thereby confirming its crucial role. Mice expressing Elf2a or Elf2b in haemopoietic cells variously displayed perturbations in the pre-B cell stage and multiple stages of T cell development. Mature B cells, T cells, and myeloid cells in steady state were unaffected, suggesting that the main role of ELF2 is restricted to the early development of B and T cells and that compensatory mechanisms exist. No differences in B and T cell development were observed between ELF2 isoforms. We conclude that ELF2 isoforms are important regulators of cellular proliferation, cell cycle progression, and apoptosis. In respect to this, ELF2B acts in a dominant negative fashion compared to ELF2A and as a putative tumour suppressor gene. Given that these cellular processes are critical during haemopoiesis, we propose that the regulatory interplay between ELF2 isoforms contributes substantially to early B and T cell development.
Patterns of familial cancer clustering in Asian cancer patients.
Authors: Joline Si Jing Lim, Pei Yi Ong, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2014)

e12528 Background: About 10-15% of patients develop cancer due to a genetic predisposition, but only a fraction is due to defined syndromes with known causative genes. Routine detailed collection of family history (FH) may yield useful information on the frequency and patterns of familial cancer clustering. Methods: A 3-generation FH was collected from cancer patients in a tertiary centre in Asia from 2001 to 2013 using a self-completed questionnaire. A genogram was constructed by a trained cancer genetics counselor and reviewed for hereditary cancer syndromes (HCS). Results: Of 7,104 patients included, majority were female (66.3%) and Chinese (80.5%). 13.8% were diagnosed at age <40, 2.8% had >1 primary cancer, 39.5% had FH of cancer, of which 74.5% (2,095/2,805) had ≥1 affected first degree relative (FDR). The most common cancers of index patients were breast, colon, lung, nasopharyngeal (NPC) and gastric (39.2%, 16.7%, 10.4%, 5.4%, 4.4%). 73% of genograms were not suspicious of HCS, 16.9% were suspicious of at least 1 HCS with known causative genes, 9.9% had clustering suggestive of a HCS but not typical of known syndromes. Hereditary breast and ovarian cancer (n=682, 9.6%), Lynch (n=448, 6.3%), hereditary diffuse gastric (n=35, 0.5%), Cowden (n=23, 0.3%) and Li Fraumeni (n=19, 0.3%) were the most common suspected known HCS. Of 702 patients with suspected unknown HCS, 84.2% had FH of cancer, 20.1% had cancer at age <40, and 11.7% had >1 primary cancer; 16.4% had ≥2 above traits. Compared to patients with suspected known HCS, patients with suspected unknown HCS were more likely to report ≥1 affected FDR with cancer (OR 2.04±0.43, p<0.001). Familial clustering of NPCs (n=45), NPC with breast (n=61), NPC with colon (n=26), and liver with breast cancers (n=51) were commonly observed, accounting for 26.1% of suspected unknown HCS. Of note, patients with familial clustering of NPCs were younger (39.2 vs 45.8 years, p<0.001) and had a stronger FH (mean number of relatives with cancer 2.35 vs 1.04, p<0.001) than index NPC patients without familial clustering. Conclusions: About a quarter of Asian cancer patients report personal or family history suggestive of known or unknown HCS, including unique patterns of familial cancer clustering that warrant further characterization.
Phase I/II trial of dose reduced capecitabine in elderly or frail patients with untreated advanced colorectal cancer.
Authors: Daniel Adam Breadner, Stephen Welch, Derek J. Jonker, Paul Klimo, M. Christine Cripps, James Joseph Biagi, Wendy Lam, Frances Whiston, Larry Stitt, Mark David Vincent
Journal: Journal of Clinical Oncology (2017)

745 Background: Capecitabine (Cape) was initially assessed at a dose of 2500 mg/m 2 in young or robust patients that do not represent the population in which oncologists consider Cape monotherapy in advanced colorectal cancer (aCRC). In practice Cape is frequently given to elderly or frail patients at 2000 mg/m 2 but the optimal dosing remains controversial. Methods: A multi-centered phase I/II trial of reduced dose Cape 2000 mg/m 2 d1–14 q21d was conducted in 221 patients in one or more of the following subsets: age65 years (167 pts), ECOG PS 1 (139 pts), elevated LDH (105 pts), prior pelvic RT (54 pts). Results: Median age was 72 years. A median 5 and mean 8 cycles were given (range 0 to 50). The phase I portion of the study determined prior pelvic radiation required dose reduction to 1500 mg/m 2 for diarrhea. Grade 3/4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). Dose reductions were required in 14% and dose delays in 21%. Response rate is 13.6%, with 69.7% disease control rate. Median PFS was 5.6 months. Post progression 125 patients (67%) received further chemotherapy, 56 received further Cape monotherapy with a median of 4 additional cycles. Median overall survival for all patients is 14.3 months. Median survival was significantly higher for baseline ECOG 0 vs. ≥ 1 and normal vs. elevated LDH. When comparing patients receiving 2000 compared to 1500 mg/m 2 the ORR was 19% vs. 17%, and the DCR was 73% vs. 63%. Median PFS was 5.9 vs. 4.7 months, and the OS was equal at 14.3 months. Hand-foot syndrome was more common at the higher dose, 46% vs. 30%, any grade. Conclusions: This report suggests dose reduced Cape has less toxicity compared to full dose, with only a small tradeoff in efficacy seen as a lower ORR. However, its improved tolerability likely leads to an increased number of cycles of therapy, and the PFS seems consistently higher at the lower dose. This trial reduces uncertainty regarding further dose reductions to 1500 mg/m 2 for frail patients, in whom quality of life may be paramount. This should be viewed as compelling evidence, in the absence of a head to head clinical trial, that 2000, or even 1500, mg/m 2 is an appropriate dose in elderly or frail patients with aCRC.
Prospective randomized crossover study of effects of traditional Japanese herbal medicine rikkunshito on food intake and plasma acylated ghrelin levels in patients with esophageal cancer administered with cisplatin-based chemotherapy.
Authors: Yoichi Hamai, Tomoharu Yoshiya, Manabu Emi, Takaoki Furukawa, Yuta Ibuki, Morihito Okada
Journal: Journal of Clinical Oncology (2017)

133 Background: Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces chemotherapy-induced nausea and vomiting (CINV). Acylated ghrelin (AG) is an orexigenic gut hormone that can alleviate CINV. We evaluated whether rikkunshito (RKT), a traditional Japanese herbal medicine with an orexigenic effect, can improve CINV-induced anorexia and increase levels of plasma AG in patients with esophageal cancer administered with CDDP-based chemotherapy. Methods: This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy between July 2013 and March 2016. Tenof them were assigned to group A (1st course with 7.5 g/day RKT on days 1 - 14; 2nd course without RKT [control]) and 10 were assigned to group B (1st course without RKT [control]; 2nd course with RKT). Food intake and levels of plasma AG (fmol/mL) were compared between the control and RKT courses. Results: Data from 18 of the patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patients and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6, which is associated with delayed-onset CINV, was considerably lower in the groups given RKT than in the control (2% vs. 30%; p = 0.07). Median levels of AG significantly decreased between days 1 to 3 in the group given RKT (15.1 to 9.6 fmol/mL, p = 0.001) and the control (14.1 to 10.2, p = 0.003), and then obviously increased from days 3 to 8 in patients with both courses (RKT: 9.6 to 15.7 fmol/mL, p &lt; 0.0001; control: 10.2 to 17.8, p = 0.0002). However, the rate at which median plasm AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control group (68% vs. 48%, p = 0.08). Conclusions: RKT might improve delayed-onset CINV as well as CINV-induced anorexia and increases in plasma AG levels among patients with esophageal cancer who undergo highly emetogenic CDDP-based chemotherapy. Clinical trial information: UMIN000010747.