tbuckley/cabot-search huggingface dataset:
Prognostic implications of signet ring cell histology in esophageal adenocarcinoma: A SEER database analysis
Authors: Saikrishna S. Yendamuri, Miriam Huang, Usha Malhotra, Graham Walter Warren, Paul Bogner, Chukwumere E. Nwogu, Adrienne Groman, Todd L. Demmy
Journal: Journal of Clinical Oncology (2013)

4067 Background: Signet ring cell esophageal adenocarcinoma histology has been difficult to study in a single institution series because of its relative rarity, yet has an anecdotal reputation for poor prognosis. We examined the Surveillance Epidemiology and End Results (SEER) database to assess the prognostic implications of this esophageal adenocarcinoma subtype. Methods: All patients with esophageal adenocarcinoma in the SEER database from 2004 – 2009 were included. Characteristics of patients with signet ring cell histology were compared to those without it. Univariate and multivariate analyses examining the relationship of signet ring cell histology with overall survival (censored at 72 months) were performed in all patients, as well as those undergoing surgical resection. Results: 597 of 11,838 (5%) study patients had signet ring cell histology. Patients with signet ring cell histology were similar in age, race, and gender distribution, but had a higher grade (p&lt;0.001) and higher stage (p&lt;0.001) at diagnosis. In both all-comers as well as those undergoing surgical resection, univariate analyses showed a worse survival in patients with signet ring cell esophageal cancer (HR = 1.24; 95% CI 1.13-1.37 and HR = 1.57; 95% CI 1.29-1.92 respectively). In multivariate analyses adjusting for age, gender, grade, stage, and race, patients with signet ring cell cancer had a worse prognosis than those with non-signet ring cell adenocarcinoma (HR = 1.20; 95% CI 1.09 -1.33). In surgically resected patients, this remained a trend, but did not reach statistical significance (HR = 1.16; 95% CI 0.94-1.42). Conclusions: This large study of esophageal adenocarcinoma confirms the clinical impression that signet ring cell variant of adenocarcinoma is associated with an advanced stage at presentation and a worse prognosis independent of stage of presentation.
A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX® (Methoxsalen) for National Institutes of Health (NIH)-Graded Moderate to Severe Chronic Graft-Vs-Host Disease (cGVHD)
Authors: Madan Jagasia, Hildegard T. Greinix, Christof Scheid, Gérard Socié, Francis A Ayuk, Johanna Tischer, Michele L. Donato, Arpad Batai, Thomas Chin, Henri William Boodee, Ghaith Mitri
Journal: Blood (2017)
Safety and efficacy of dicarbamin in patients with early breast cancer receving DAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy in adjuvant setting.
Authors: Mikhail V. Kopp, Irina Koroleva, Anastasia Mochalova, Leonid Shaplygin
Journal: Journal of Clinical Oncology (2013)

e12012 Background: One of the most serious potential side effects of chemotherapy is neutropenia. Grade 3 and 4 neutropenia is especially problematic because of increased incidence of infections, hospitalization, antibiotic treatment, necessity to reduce therapy intensity. The intensity of adjuvant chemotherapy is the key to successful treatment. Dicarbamin is agent for the prevention of chemotherapy-induced neutropenia. Dicarbamin therapy decreases dystrophic changes in myeloid progenitor cells and decreases the relative number of cells with signs of apoptosis. We conducted an analysis of efficacy of dicarbamin in patients during docetaxel-based chemotherapy. Methods: Between May 2011 and July 2012, 87 patients with early breast cancer were treated with adjuvant DAC regimens (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 every 3 weeks). All patients were female. All patients were treated with these regimens without prophylactic growth factor support. 42 patients of control (group A) were not given any prophylaxis of neutropenia. 45 patients (group B) were given dicarbamin 100 mg/day on day 5 before chemotherapy administration. Treatment with dicarbamin continued for all treatment period. Neutropenia was evaluated with Common Toxicity Criteria, Version 3.0. Results: Median age was 47 (29 – 55). Grade 4 neutropenia was reported in 13 (30.9%) patients treated without dicarbamin (A) and in 8 (17.7%) patients treated with dicarbamin (B). Grade 4 neutropenia was observed in 39 cycles in group A and in 22 cycles in group B (p=0.016). The beneficial effect of dicarbamin was also demonstrated by a quick recovery of granulocytes levels than in controls. In 17 (37.7%) patients treated with dicarbamin granulocytes levels were normal all period of chemotherapy. The dose intensity of chemotherapy was more in group with dicarbamin prophilaxis. The toxicity of dicarbamin was not observed. Conclusions: Dicarbamin is an active agent for prophylaxis of neutropenia without specific toxicity. The intensity of the DAC-chemotherapy was more in group with dicarbamin prophilaxis.
A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), a Novel Inhibitor of Aurora Kinase a, in Myelofibrosis
Authors: Naseema Gangat, Ronan T. Swords, Brady Lee Stein, Christian Marinaccio, Justin M Watts, Olga Frankfurt, Jessica K. Altman, Aref Al-Kali, Darci Zblewski, Sandeep Gurbuxani, Jeremy Q. Wen, Roberto Tapia, Stephanie Barath, Amy Graf, Amy Handlogten, Yvonne Trang Dinh, Kristen Englund, Shradha Patel, Orlando Bodes, Jillian Ogden, Francis J. Giles, Ayalew Tefferi, John D. Crispino
Journal: Blood (2017)
Transcriptional Enhancers in the FOXP2 Locus Underwent Accelerated Evolution in the Human Lineage
Authors: Alfredo Leandro Caporale, Catalina M Gonda, Lucía Florencia Franchini
Journal: Molecular Biology and Evolution (2019)

Unique human features, such as complex language, are the result of molecular evolutionary changes that modified developmental programs of our brain. The human-specific evolution of the forkhead box P2 (FOXP2) gene-coding region has been linked to the emergence of speech and language in the human kind. However, little is known about how the expression of FOXP2 is regulated and whether its regulatory machinery evolved in a lineage-specific manner in humans. In order to identify FOXP2 regulatory regions containing human-specific changes, we used databases of human-accelerated noncoding sequences or HARs. We found that the topologically associating domain determined using developing human cerebral cortex containing the FOXP2 locus includes two clusters of 12 HARs, placing the locus occupied by FOXP2 among the top regions showing fast acceleration rates in noncoding regions in the human genome. Using in vivo enhancer assays in zebrafish, we found that at least five FOXP2-HARs behave as transcriptional enhancers throughout different developmental stages. In addition, we found that at least two FOXP2-HARs direct the expression of the reporter gene EGFP to foxP2-expressing regions and cells. Moreover, we uncovered two FOXP2-HARs showing reporter expression gain of function in the nervous system when compared with the chimpanzee ortholog sequences. Our results indicate that regulatory sequences in the FOXP2 locus underwent a human-specific evolutionary process suggesting that the transcriptional machinery controlling this gene could have also evolved differentially in the human lineage.
A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).
Authors: Sue Richter, Elaine McWhirter, Eric Xueyu Chen, Ben Tran, Sebastien J. Hotte, Anastasios Stathis, Hal W. Hirte, Albiruni R.A. Razak, Anne Laughlin, Lisa Wang, Kristina Battista, Lee-Anne Stayner, S. Percy Ivy, Malcolm J. Moore, Amit M. Oza, Lillian L. Siu, Philippe Bedard
Journal: Journal of Clinical Oncology (2012)

3082 Background: RO4929097 (RO) is an oral inhibitor of γ-secretase that disrupts Notch signaling. Gemcitabine (GEM) is active against many solid tumors with a favorable toxicity profile suited to combination. The primary objective of this trial is to establish the recommended phase II dose (RP2D) of RO in combination with GEM; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics (PK), biomarkers of Notch signaling and preliminary anti-tumor activity. Methods: Patients (pts) with advanced solid tumors were enrolled in escalating RO dose levels (DL) as follows: DL1 20mg, DL2 30mg; DL3 45mg and DL4 90mg using a 3+3 design. Treatment with RO was administered once daily on days (d) 1-3, 8-10, 15-17, 22-24 and GEM 1000mg/m 2 on d1, 8, and 15 in 28d cycles (c). Dose limiting toxicities (DLTs) during c1 were defined as CTCAE v4 grade (g) 3 non-hematological or g4 hematological toxicities, failure to start c2 within &lt;14 days, or failure to receive ≥75% doses of RO or d8 GEM in c1. Serial plasma samples for RO PK were collected on d1 and 10. Results: As of January 2012, 15 pts (median age 55) have been treated. DLTs were: DL1 0/3, DL2 1/7 (g3 ALT), DL3 0/3, DL4 2/2 (g3 AST/ALT and failure to receive ³75% doses); all were reversible. One death (perforated viscus) related to disease progression was observed. Most common g1/2 toxicities were nausea (9), vomiting (6), fatigue (5), hypophosphatemia (5), transaminitis (3) hypomagnasemia (2) and maculopapular rash (2). G3 hypophosphatemia (1) was observed beyond C1. RO PKs demonstrated comparable exposures at 30mg and 45mg (Table). Best response (RECIST 1.1) was stable disease &gt; 4 months in 3 pts (pancreas, tracheal, breast CA). Conclusions: RO and GEM can be safely combined. RO levels achieved exceeded the AUC 0-24 for efficacy in preclinical models using daily dosing. The maximum tolerated dose was exceeded at 90mg RO. Dose expansion at 45mg RO is ongoing to confirm the RP2D. [Table: see text]
Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics
Authors: Takahiro Masuda, Fuminari Misawa, Masayuki Takase, John M. Kane, Christoph U. Correll
Journal: JAMA Psychiatry (2019)

Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice.To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies.Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018.Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder.Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data.Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies.Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90).In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.
Nomogram to estimate the activity of second-line therapy for advanced urothelial carcinoma (UC).
Authors: Guru Sonpavde, Gregory Russell Pond, Neeraj Agarwal, Toni K. Choueiri, Angela Q. Qu, Ronan Fougeray, Yacine Salhi, David J. Vaughn, Nicholas David James, Guenter Niegisch, Peter Albers, Matt D. Galsky, Yu-Ning Wong, Walter Michael Stadler, Peter H. O'Donnell, Nicholas J. Vogelzang, Srikala S. Sridhar, Yoo-Joung Ko, Cora N. Sternberg, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2013)

4524 Background: Prognostic factors may impact on endpoints used in phase II trials of second-line therapy for advanced UC. We aimed to study the impact of prognostic factors (liver metastasis [LM], anemia [Hb&lt;10 g/dl], ECOG-performance status [PS] ≥1, time from prior chemotherapy [TFPC]) on PFS6 and RR. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n=748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. RR was defined using RECIST 1.0. A nomogram predicting PFS6 was constructed using the RMS package in R (www.r-project.org). Results: Data regarding progression, Hb, LM, PS and TFPC were available from 570 patients. The mean age was 65.1 years, 45.3% had ECOG-PS ≥1, 30.2% had LM, 14.6% had anemia and TFPC was &lt;6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%-20.9%). For every unit increase in risk group, the hazard of progression increased by 41% and the odds of response decreased by 48% (Table). A nomogram was constructed to predict PFS6 on an individual patient level. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors might facilitate the evaluation of activity across phase II trials enrolling heterogeneous populations and can help to select and stratify patients for phase III evaluation of suitable agents. [Table: see text]
Mutations in ANXA11 cause familial and sporadic amyotrophic lateral sclerosis
Authors: B N Smith, S Topp, C Fallini, Chen H-J., C Troakes, A King, N Ticozzi, K P Kenna, A Sato, A Soragia-Gkazi, J Miller, C Vance, Wong C-H., M de Majo, W Kuttuah, J C Mitchell, E L Scotter, N Parkin, P C Sapp, M Nolan, P J Nestor, M Simpson, F Baas, de Jong Vjm., ten Asbroek Alma., A G Redondo, J Esteban-Perez, J L Munoz-Blanco, C Tiloca, F Verde, S Dugo, P N Leigh, H Pall, K E Morrison, A Al-Chalabi, P J Shaw, J Kirby, M R Turner, K Talbot, O Hardiman, J D Glass, J de Belleroche, M Maki, S Moss, C Miller, C Gellera, A Ratti, S Al-Sarraj, Brown Rhj., V Silani, J E Landers, C E Shaw
Journal: Science Translational Medicine (2017)
A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Han Sang Kim, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2012)

e18080 Background: Nimotuzumab (TheraCIM) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Methods: Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100 mg or 200 mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We designed to enroll additional 10 patients at RPIID for the safety analysis. EGFR mutations and KRAS mutations were analyzed from available tumor samples. Results: A total of 16 patients were enrolled (3 in 100 mg cohort, 13 in 200 mg cohort). Six patients (40%) were female, and 5 (33.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%).Treatment was well-tolerated without dose-limiting toxicity (DLT). Three patients (18.7%) experienced grade 2 skin toxicity (1 in 100 mg cohorts, 2 in 200 mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (28.6%) achieved partial response and 5patients (35.7%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Conclusions: Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC.
Patient and health system disparities in timeliness of treatment for individuals with colorectal cancer (CRC)
Authors: M. T. Halpern, D. J. Holden
Journal: Journal of Clinical Oncology (2009)

6540 Background: Timely initiation of treatment following cancer diagnosis can improve morbidity, quality of life, and survival. We used SEER-Medicare data for individuals diagnosed with CRC to explore disparities in the timeliness of initial cancer therapy. Methods: Medicare patients diagnosed with CRC in 2000–2001 while living in SEER regions were identified. Only patients who received cancer treatment (surgery, radiation therapy, or chemotherapy), were diagnosed at age 66 or later, and were enrolled in Medicare at least one year post-diagnosis were included. Multivariate logistic regression analysis was used to evaluate the impact of patient sociodemographic, clinical, community, and health system factors on receipt of timely care, defined as treatment initiation within the 95 th percentile of waiting time for all CRC patient (two months). Results: Black and Hispanic CRC patients were significantly more likely to experience delays in treatment than were White patients. Males and patients from areas with more non-English speakers were also more likely to experience delays. Among earlier stage patients who received surgery, those treated at physician offices (10.2%) were significantly more likely to experience delays than were those treated at hospitals (as inpatients or outpatients). Among patients with distant stage disease, those initially treated as hospital inpatients were significantly less likely to experience delays than were those treated as hospital outpatients or in physician offices. For these patients, initial treatment with chemotherapy or radiation therapy was associated with significantly greater likelihood of delays compared to patients initially receiving surgery. Conclusions: Controlling for other factors, significant disparities in timeliness of care were observed for racial/ethnic minority patients, males, and those from non-English speaking areas. Treatment site and modality also affected timeliness of care. While more research is needed, programs should target these at-risk populations for education and follow-up after diagnosis. No significant financial relationships to disclose.
A phase II, multicenter, open-label study of YM155 plus docetaxel in subjects with stage III (unresectable) or stage IV melanoma.
Authors: Joyce Leta Steinberg, Agop Y. Bedikian, D. Scott Ernst, Bartosz Chmielowski, Bruce Redman, Anne Therese Keating, Fei Jie, Caroline Chen, Jeffrey S. Weber, Ragini Reiney Kudchadkar
Journal: Journal of Clinical Oncology (2012)

8587 Background: Survivin is a microtubule-associated protein implicated in both preservation of cell viability and regulation of mitosis in tumor cells. It is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: Part 1 established the dose of docetaxel that was tolerable in combination withYM155 at 5 mg/m 2 /day continuous infusion over 168 hours q 3 weeks. Part 2 utilized the dose of docetaxel established in Part 1 to further evaluate the tolerability and activity of the combination. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were overall response rate, 1-year overall survival (OS), time from first response to progression, clinical benefit rate, time to response, and safety. Results: 64 patients with metastatic melanoma were treated with docetaxel followed by continuous infusion YM155. 7 patients were treated with 100mg/m 2 of docetaxel and 57 patients were treated with 75mg/m 2 of docetaxel. Median age was 59, with 44 men and 20 women treated. 6-month PFS per Independent Review Committee (IRC) was 34.8% (95% CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with no complete responses (CR) and 8 patients with partial responses (PR). The Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR + PR + SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities occurring in greater than 5% of patients treated included neutropenia (59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all attributable to disease progression. Conclusions: YM155 is a novel agent that shows modest activity when combined with docetaxel in patients with melanoma. YM155 was generally well tolerated, but the pre-determined primary endpoint for efficacy was not achieved.